Antibacterial agents

ABSTRACT

Quinoline and naphthyridine derivatives useful in the treatment of bacterial infections in mammals, particularly humans.

FIELD OF THE INVENTION

This invention relates to novel compounds, compositions containing themand their use as antibacterials.

BACKGROUND OF THE INVENTION

The emergence of pathogens resistant to known antibiotic therapy isbecoming a serious global healthcare problem (Chu, et al., (1996) J.Med. Chem., 39: 3853-3874). Thus, there is a need to discover new broadspectrum antiobiotics useful in combating multidrug-resistant organisms.Importantly, it has now been discovered that certain compounds haveantibacterial activity, and, therefore, may be useful for the treatmentof bacterial infections in mammals, particularly in humans.

WO0208224, WO0256882, WO02/40474 and WO02/72572 disclose quinoline andnaphthyridine derivatives having antibacterial activity.

SUMMARY OF THE INVENTION

This invention comprises compounds of the formula (I), as describedhereinafter, which are useful in the treatment of bacterial infections.It has surprisingly been found that quinoline and naphthyridinederivatives with a chloro or fluoro substituent in the 3-position haveenhanced antibacterial activity over those derivatives that areunsubstituted in the 3-position. Quinoline and naphthyridine derivativeswith a chloro group in the 3-position showed a 2 fold reduction in MIClevels against one or more of the following organisms, Staphylococcus.aureus, Staphylococcus pneumoniae, Staphylococcus. pyogenes,Enterococcus faecalis, Haemophilus influenzae, E. coli, and Moraxellacatarrhalis Ravasio. Quinoline and naphthyridine derivatives with afluoro group in the 3-position showed a 2 to 4 fold reduction in MIClevels against one or more of the following organisms, Staphylococcus.aureus, Staphylococcus pneumoniae, Staphylococcus. pyogenes,Enterococcus faecalis, Haemophilus influenzae, E. coli, and Moraxellacatarrhalis Ravasio. This invention is also a pharmaceutical compositioncomprising a compound according to formula (I) and a pharmaceuticallyacceptable carrier. This invention is also a method of treatingbacterial infections in mammals, particularly in humans.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof:

wherein:

-   Z₁ is N or CR^(1a);-   R¹ and R^(1a) are independently selected from H, nitro, halogen,    (C₁₋₃)alkylthio, (C₁₋₃)alkyl, and (C₁₋₃)alkoxy optionally    substituted by (C₁₋₃)alkoxy; or R¹ and R^(1a) are joined together to    form ethylenedioxy;-   R^(1b) is H or halogen;-   with the proviso that when Z₁ is N, then R^(1b) is H and when Z₁ is    CR^(1a) then R¹ is not H;-   R^(1c) is halogen;-   AB is CHR⁶—CO or CHR⁶—CH₂;-   R⁶ is H, NH₂, —CH₂OH, or hydroxy;-   R³ is up to two substituents selected from H, halogen, (C₁₋₃)alkyl,    hydroxy(C₁₋₃)alkyl, CONH₂, COOH, —CH₂CONH₂, —CH₂COOH, —CONHCH₃, and    hydroxy in the 3-position optionally substituted by (C₁₋₃)alkyl;-   R⁴ is a group —U—R⁵ where R⁵ is a substituted or unsubstituted    bicyclic carbocyclic or heterocyclic ring system (A):    containing up to four heteroatoms in each ring in which    -   at least one of rings (a) and (b) is aromatic;    -   X¹ is C or N when part of an aromatic ring or CR¹⁴ when part of        a non aromatic ring;    -   X² is N, NR¹³, O, S(O)_(x), CO or CR¹⁴ when part of an aromatic        or non-aromatic ring or may in addition be CR¹⁴R¹⁵ when part of        a non aromatic ring;    -   X³ and X⁵ are independently N or C;    -   Y¹ is a 0 to 4 atom linker group each atom of which is        independently selected from N, NR¹³, O, S(O)_(x), CO and CR¹⁴        when part of an aromatic or non-aromatic ring or may        additionally be CR¹⁴R¹⁵ when part of a non aromatic ring,    -   Y² is a 2 to 6 atom linker group, each atom of Y² being        independently selected from N, NR¹³, O, S(O)_(x), CO and CR¹⁴        when part of an aromatic or non-aromatic ring or may        additionally be CR¹⁴R¹⁵ when part of a non aromatic ring;    -   each of R¹⁴ and R¹⁵ is independently selected from H;        (C₁₋₄)alkylthio; halo; (C₁₋₄)alkyl; (C₂₋₄)alkenyl; hydroxy;        hydroxy(C₁₋₄)alkyl; mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy;        trifluoromethoxy; nitro; cyano; carboxy; amino or aminocarbonyl        optionally substituted by (C₁₋₄)alkyl;    -   each R¹³ is independently H; trifluoromethyl; (C₁₋₄)alkyl        optionally substituted by hydroxy, carboxy, (C₁₋₄)alkoxy,        (C₁₋₆)alkylthio, halo or trifluoromethyl; (C₂₋₄)alkenyl; or        aminocarbonyl wherein the amino group is optionally substituted        (C₁₋₄)alkyl;    -   each x is independently 0, 1 or 2; and    -   U is CO, SO₂ or CH₂; or a pharmaceutically acceptable salt        thereof.

Also included in this invention are pharmaceutically acceptable additionsalts, complexes or prodrugs of the compounds of this invention.Prodrugs are considered to be any covalently bonded carriers whichrelease the active parent drug according to formula (I) in vivo.

The invention also provides a pharmaceutical composition, in particularfor use in the treatment of bacterial infections in mammals,particularly humans, comprising a compound of formula (I), or apharmaceutically acceptable derivative thereof, and a pharmaceuticallyacceptable carrier.

The invention further provides a method of treatment of bacterialinfections in mammals, particularly in humans, which method comprisesthe administration to a mammal in need of such treatment an effectiveamount of a compound of formula (I), or a pharmaceutically acceptablederivative thereof.

Preferably R¹ is F, Cl, OCH₃, methyl, or SCH₃ Most preferably R¹ is F,Cl, or OCH₃.

Preferably, R^(1a) is H, OCH₃, or OCH₂CH₂OCH₃. Most preferably R^(1a) isH or —OCH₃.

Preferably, R^(1b) is H or F. Most preferably R^(1b) is H.

Preferably, R^(1c) is Cl or F.

Preferably R³ is H, OH, OCH₃, or CH₂OH.

Preferably AB is CHR⁶—CH₂.

Preferably R⁶ is H or OH.

The group —U— is preferably —CH₂—.

Preferably R⁵ is an aromatic heterocyclic ring (A) having 8-11 ringatoms including 2-4 heteroatoms of which at least one is N or NR¹³, inwhich preferably Y² contains 2-3 heteroatoms, one of which is S and 1-2are N, with one N bonded to X³.

Alternatively and preferably the heterocyclic ring (A) has ring (a)aromatic selected from optionally substituted benzo and pyrido and ring(b) non-aromatic and Y² has 3-5 atoms including a heteroatom bonded toX⁵ selected from NR¹³, O or S and NHCO bonded via N to X³, or O bondedto X³. Examples of rings (A) include optionally substituted:

-   (a) and (b) Aromatic-   1H-pyrrolo[2,3-b]-pyridin-2-yl, 1H-pyrrolo[3,2-b]-pyridin-2-yl,    3H-imidazo[4,5-b]-pyrid-2-yl, 3H-quinazolin-4-one-2-yl,    benzimidazol-2-yl, benzo[1,2,3]-thiadiazol-5-yl,    benzo[1,2,5]-oxadiazol-5-yl, benzofur-2-yl, benzothiazol-2-yl,    benzo[b]thiophen-2-yl, benzoxazol-2-yl, chromen-4-one-3-yl,    imidazo[1,2-a]pyridin-2-yl, imidazo-[1,2-a]-pyrimidin-2-yl,    indol-2-yl, indol-6-yl, isoquinolin-3-yl, [1,8]-naphthyridine-3-yl,    oxazolo[4,5-b]-pyridin-2-yl, quinolin-2-yl, quinolin-3-yl,    quinoxalin-2-yl, indan-2-yl, naphthalen-2-yl,    1,3-dioxo-isoindol-2yl, benzimidazol-2-yl, benzothiophen-2-yl,    1H-benzotriazol-5-yl, 1H-indol-5-yl, 3H-benzooxazol-2-one-6-yl,    3H-benzooxazol-2-thione-6-yl, 3H-benzothiazol-2-one-5-yl,    3H-quinazolin-4-one-2-yl, 3H-quinazolin-4-one-6-yl,    4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl, benzo[1,2,3]thiadiazol-6-yl,    benzo[1,2,5]thiadiazol-5-yl, benzo[1,4]oxazin-2-one-3-yl,    benzothiazol-5-yl, benzothiazol-6-yl, cinnolin-3-yl,    imidazo[1,2-a]pyridazin-2-yl, imidazo[1,2-b]pyridazin-2-yl,    pyrazolo[1,5-a]pyrazin-2-yl, pyrazolo[1,5-a]pyridin-2-yl,    pyrazolo[1,5-a]pyrimidin-6-yl, pyrazolo[5,1-c][1,2,4]triazin-3-yl,    pyrido[1,2-a]pyrimdin-4-one-2-yl, pyrido[1,2-a]pyrimidin-4-one-3-yl,    quinazolin-2-yl, quinoxalin-6-yl,    thiazolo[3,2-a]pyrimidin-5-one-7-yl, thiazolo[5,4-b]pyridin-2-yl,    thieno[3,2-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-6-yl,    4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl,    1-oxo-1,2-dihydro-isoquinolin-3-yl, thiazolo[4,5-b]pyridin-5-yl,    [1,2,3]thiadiazolo[5,4-b]pyridin-6-yl, 2H-isoquinolin-1-one-3-yl-   (a) is Non Aromatic-   (2S)-2,3-dihydro-1H-indol-2-yl,    (2S)-2,3-dihydro-benzo[1,4]dioxine-2-yl,    3-(R,S)-3,4-dihydro-2H-benzo[1,4]thiazin-3-yl,    3-(R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl,    3-(S)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl,    2,3-dihydro-benzo[1,4]dioxan-2-yl,    3-substituted-3H-quinazolin-4-one-2-yl,    2,3-dihydro-benzo[1,4]dioxan-2-yl,    1-oxo-1,3,4,5-tetrahydrobenzo[c]azepin-2-yl.-   (b) is Non Aromatic-   1,1,3-trioxo-1,2,3,4-tetrahydro-1 I⁶-benzo[1,4] thiazin-6-yl,    benzo[1,3]dioxol-5-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl,    2-oxo-2,3-dihydro-benzooxazol-6-yl, 4H-benzo[1,4]oxazin-3-one-6-yl    (3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl),    4H-benzo[1,4]thiazin-3-one-6-yl    (3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl),    4H-benzo[1,4]oxazin-3-one-7-yl,    4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepine-7-yl,    5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-6-yl,    benzo[1,3]dioxol-5-yl,    2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl,    2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-yl,    3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl,    2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl,    2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl,    2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl,    6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidin-2-yl,    3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl,    2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-7-yl,    2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,    6-oxo-6,7-dihydro-5H-8-thia-1,2,5-triaza-naphthalen-3-yl,    3,4-dihydro-2H-benzo[1,4]oxazin-6-yl,    3-substituted-3H-benzooxazol-2-one-6-yl,    3-substituted-3H-benzooxazole-2-thione-6-yl,    3-substituted-3H-benzothiazol-2-one-6-yl,    2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl,    3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,    3,4-dihydro-1H-quinolin-2-one-7-yl,    3,4-dihydro-1H-quinoxalin-2-one-7-yl,    6,7-dihydro-4H-pyrazolo[1,5-a]pyrimidin-5-one-2-yl,    5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl,    2-oxo-3,4-dihydro-1H-[1,8]naphthyridin-6-yl,    3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl.

R¹³ is preferably H if in ring (a) or in addition (C₁₋₄)alkyl such asmethyl or isopropyl when in ring (b). More preferably, in ring (b) R¹³is H when NR¹³ is bonded to X³ and (C₁₋₄)alkyl when NR¹³ is bonded toX⁵.

R¹⁴ and R¹⁵ are preferably independently selected from hydrogen, halo,hydroxy, (C₁₋₄) alkyl, (C₁₋₄)alkoxy, trifluoromethoxy; nitro, cyano,aryl(C₁₋₄)alkoxy and (C₁₋₄)alkylsulphonyl.

More preferably R¹⁵ is hydrogen.

More preferably each R¹⁴ is selected from hydrogen, chloro, fluoro,hydroxy, methyl, methoxy, trifluoromethoxy, benzyloxy, nitro, cyano andmethylsulphonyl. Most preferably R¹⁴ is selected from hydrogen, hydroxy,fluorine or nitro. Preferably 0-3 groups R¹⁴ are substituents other thanhydrogen.

Preferred groups R⁵ include:

-   [1,2,3]thiadiazolo[5,4-b]pyridin-6-yl,-   1H-Pyrrolo[2,3-b]pyridin-2-yl,-   2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl,-   2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl,-   2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl,-   2,3-dihydro-benzo[1,4]dioxin-6-yl,-   2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,-   2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl,-   3,4-dihydro-2H-benzo[1,4]oxazin-6-yl,-   3-Methyl-2-oxo-2,3-dihydro-benzooxazol-6-yl,-   3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl,-   3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl,-   4H-benzo[1,4] thiazin-3-one-6-yl,-   4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl,-   6-nitro-benzo[1,3]dioxol-5-yl,-   7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl,-   8-Hydroxy-1-oxo-1,2-dihydro-isoquinolin-3-yl,-   8-hydroxyquinolin-2-yl,-   benzo[1,2,3]thiadiazol-5-yl,-   benzo[1,2,5]thiadiazol-5-yl,-   benzothiazol-5-yl,-   thiazolo-[5,4-b]pyridin-6-yl,-   3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl,-   7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl,-   7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl, and-   2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-yl,-   2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-yl,-   6-oxo-6,7-dihydro-5H-pyridazino[3,4-b][1,4]thiazin-3-yl,-   2,3-dihydro[1,4]oxathiino[2,3-c]pyridin-7-yl,-   [1,3]oxathiolo[5,4-c]pyridin-6-yl,-   4-fluoro-1H-benzimidazol-2-yl,-   cinnolin-3-yl,-   1,5,6,7-tetrahydro-1,8-naphthyridin-2-yl,-   2,1,3-benzothiadiazol-5-yl,-   [1,3]thiazolo[5,4-b]pyridin-6-yl,-   1,3-benzothiazol-5-yl,-   [1,2,3]thiadiazolo[5,4-b]pyridin-6-yl,-   3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl,    2-oxo-3,4-dihydro-1,8-naphthyridin-7-yl,-   4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl,-   8-methoxy-2,3-dihydro-1,4-benzodiozin-6-yl,-   7-methyl, 2,3-dihydro-1,4-benzodioxin-6-yl,-   2,3-dihydro-1H-benzofuran-5yl,-   benzo-1,3-dioxol-5-yl, and-   1-oxo-8-methoxymethoxy-2H-isoquinolin-3-yl.

Most preferred groups R⁵ include:

-   benzo[1,2,5]thiadiazol-5-yl,-   4H-benzo[1,4] thiazin-3-one-6-yl,-   2,3-dihydro-benzo[1,4]dioxin-6-yl,-   benzo[1,2,3]thiadiazol-5-yl,-   3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl,-   7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4] oxazin-6-yl,-   2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl,-   2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl,-   3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl,-   [1,2,3]thiadiazolo[5,4-b]pyridin-6-yl,-   3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl,-   7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl,-   7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl,-   2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-yl,

Most especially preferred groups R⁵ include:

-   3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl,-   3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl, and-   2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl,

Preferred compounds of this invention include:

-   6-({1-[(Racemic)-2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one    Dihydrochloride;-   (Racemic)-1-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-{4-[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-piperidin-1-yl}-ethanol    Dihydrochloride;-   {1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amine    Dihydrochloride;-   {1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amine    Dihydrochloride;-   6-({(cis)-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one    Dihydrochloride Enantiomer 1;-   6-({(cis)-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one    Dihydrochloride Enantiomer 2;-   6-({(cis)-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one    Dihydrochloride Enantiomer 1;-   6-({(cis)-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one    Dihydrochloride Enantiomer 2;-   6-({(cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one    Dihydrochloride Enantiomer 1;-   6-({(cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one    Dihydrochloride Enantiomer 2;-   6-({(cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one    Dihydrochloride Enantiomer 1;-   6-({(cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one    Dihydrochloride Enantiomer 2;-   6-({1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-yl    amino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one Trihydrochloride;-   6-({1-[2-(3-chloro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-yl    amino}methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one Trihydrochloride;-   6-({1-[2-(3-Chloro-6-methoxynaphthyridin-4-yl)ethyl]piperidin-4-yl    amino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one Dihydrochloride;-   6-({1-[2-(3-chloro-6-methoxynaphthyridin-4-yl)ethyl]piperidin-4-yl    amino}methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one Dihydrochloride;-   6-({(trans)-1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]3-hydroxypiperidin-4-yl    amino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one Trihydrochloride    enantiomer 2;-   6-({(trans)-1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]3-hydroxypiperidin-4-yl    amino}methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one Trihydrochloride    enantiomer 2;-   6-(trans)-1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]3-hydroxypiperidin-4-yl    amino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one Trihydrochloride    enantiomer 1;-   6-(trans)-1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]3-hydroxypiperidin-4-yl    amino}methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one Trihydrochloride    enantiomer 1;-   6-({1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]4-hydroxymethylpiperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one    Dihydrochloride;-   6-({1-[2-(3-Chloro-6-fluoro-5-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one    Dihydrochloride;-   6-({1-[2-(3-Chloro-6-methyl-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one    Dihydrochloride;-   {1-[2-(3-Chloro-6-methyl-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amine    Dihydrochloride;-   6-({1-[2-(3-Chloro-6-fluoro-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one    Dihydrochloride;-   {1-[2-(3-Chloro-6-fluoro-quinolin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amine    Dihydrochloride;-   6-({1-[2-(3,6-Dichloro-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one    Dihydrochloride;-   {1-[2-(3,6-Dichloro-quinolin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl-amine    Dihydrochloride;-   (cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-4-[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-piperidin-3-ol    Dihydrochloride Enantiomer 1;-   (cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-4-[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-piperidin-3-ol    Dihydrochloride Enantiomer 2;-   6-({1-[2-(3-Fluoro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-yl    amino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one dihydrochloride;-   {1-[2-(3-Fluoro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amine    dihydrochloride;-   cis-4-[(2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-1-[2-(3-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-3-ol    Enantiomer 2 dihydrochloride;-   cis-4-[(2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-1-[2-(3-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-3-ol    dihydrochloride dihydrochloride Enantiomer 1;-   {1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxyethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amine    Dihydrochloride Enantiomer 1;-   6-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one    Dihydrochloride Enantiomer 1;-   6-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one    Dihydrochloride Enantiomer 2;-   (6-(trans)-1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]-3-hydroxypiperidin-4-yl)-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amine    Enantiomer 2;-   (trans)-6-({(1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]-thiazin-3-one    Dihydrochloride Enantiomer 2;-   trans-6-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]    oxazin-3-one Trihydrochloride Enantiomer 2;-   trans-6-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]    thiazin-3-one dihydrochloride Enantiomer 1;-   6-({(3R,4r,5S)-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3,5-dihydroxy-piperidin-4-ylamino)}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one    dihydrochloride;-   6-({1-[2-(3-Fluoro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-yl    amino}methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one dihydrochloride;-   {1-[2-(3-Bromo-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amine    Dihydrochloride;-   cis-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-4-[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-piperidin-3-ol    Dihydrochloride Enantiomer 1;-   cis-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-4-[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-piperidin-3-ol    Dihydrochloride Enantiomer 2;-   1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinamine    dihydrochloride;-   7-{[(1-{2-[3,8-Difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one    dihydrochloride;-   6-{[(1-{2-[3,8-Difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dinydrochloride;-   6-{[(1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride;-   1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-([1,3]dioxolo[4,5-c]pyridin-6-ylmethyl)-4-piperidinamine    dihydrochloride;-   {1-[2-(9-Chloro-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amine    dihydrochloride;-   N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinamine    dihydrochloride;-   N-(2,3-Dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinamine    dihydrochloride;-   6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride;-   7-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one    dihydrochloride;-   3-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-8-hydroxy-1    (2H)-isoquinolinone dihydrochloride;-   3-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-5H-pyridazino[3,4-b][1,4]thiazin-6(7H)-one    dihydrochloride;-   6-{[(1-{2-[3-Fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride;-   N-(2,3-Dihydro[1,4]oxathiino[2,3-c]pyridin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinamine    dihydrochloride;-   1-{2-[3-Fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-N-([1,3]oxathiolo[5,4-c]pyridin-6-ylmethyl)-4-piperidinamine    dihydrochloride;-   7-Fluoro-N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide    dihydrochloride;-   N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide    dihydrochloride;-   N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide;-   N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxamide;-   (3R,4S)-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinol    dihydrochloride Enantiomer 1;-   6-{[((3R,4S)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride;-   6-{[((3R,4S)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride;-   (3R,4S)-4-[(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinol    dihydrochloride;-   6-{[((3S,4R)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride Enantiomer 2;-   N-((3S,4R)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide    hydrochloride Enantiomer 2;-   7-{[((3R,4S)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one    dihydrochloride Enantiomer 1;-   6-{[((3R,4S)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride Enantiomer 1;-   (3R,4S)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinol    dihydrochloride dihydrochloride Enantiomer 1;-   6-{[((3R,4S)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride;-   N-[(4-fluoro-1H-benzimidazol-2-yl)methyl]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinamine;-   1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(1,5,6,7-tetrahydro-1,8-naphthyridin-2-ylmethyl)-4-piperidinamine    dihydrochloride;-   N-(3-cinnolinylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinamine    dihydrochloride;-   N-(2,1,3-benzothiadiazol-5-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinamine    dihydrochloride;-   1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-([1,3]thiazolo[5,4-b]pyridin-6-ylmethyl)-4-piperidinamine    dihydrochloride;-   N-(3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinamine    dihydrochloride;-   N-(1,3-benzothiazol-5-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinamine    dihydrochloride;-   1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-([1,2,3]thiadiazolo[5,4-b]pyridin-6-ylmethyl)-4-piperidinamine    dihydrochloride;-   7-{[(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one    dihydrochloride;-   N-(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinamine    dihydrochloride;-   N-(2,3-dihydro[1,4]oxathiino[2,3-c]pyridin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinamine    dihydrochloride;-   4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-methyl-4-piperidinecarboxamide    dihydrochloride;-   4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinecarboxamide    dihydrochloride;-   4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-N-methyl-4-piperidinecarboxamide    dihydrochloride;-   4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinecarboxamide    dihydrochloride;-   1-{2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-4-piperidinecarboxamide    dihydrochloride;-   (4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)methanol    dihydrochloride;-   N-[1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-(hydroxymethyl)-4-piperidinyl]-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide    hydrochloride;-   N-(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxamide    hydrochloride;-   N-(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide    hydrochloride;-   7-{[((3R,4S)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one    dihydrochloride Enantiomer 1;-   6-{[((3R,4S)-1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride Enantiomer 1;-   (3R,4S)-1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinol    dihydrochloride;-   2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl)-1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethanol    Dihydrochloride Hydrate Enantiomer 1;-   2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl)-1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethanol    Dihydrochloride Hydrate Enantiomer 2;-   racemic,cis    4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-(2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinyl)methanol    dihydrochloride;-   racemic,cis-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-(2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinecarboxylic    acid dihydrochloride;-   racemic,cis-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinecarboxamide    dihydrochloride;-   1-{2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-N-[(6-oxido-2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-yl)methyl]-4-piperidinamine    dihydrochloride;-   6-{[(1-{2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]-3-hydroxypropyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride;-   6-[({1-[2-(3,6-difluoro-4-quinolinyl)ethyl]-4-piperidinyl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride;-   1-[2-(3,6-difluoro-4-quinolinyl)ethyl]-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinamine    hydrochloride dihydrochloride;-   6-[({1-[2-(3,6-difluoro-4-quinolinyl)ethyl]-4-piperidinyl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride;-   6-{[(1-{2-[3-chloro-6-fluoro-5-(methoxy)-4-quinolinyl]-1-methylethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride;-   1-{2-[3-chloro-6-fluoro-5-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinamine    dihydrochloride;-   1-[2-(6-chloro-3-fluoro-4-quinolinyl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-N-methyl-4-piperidinecarboxamide    dihydrochloride;-   2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}-1-[3-fluoro-6-(methoxy)-4-quinolinyl]ethanol    dihydrochloride Enantiomer 2;-   6-{[trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride Enantiomer E2;-   6-{[trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride Enantiomer E2;-   trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinol    dihydrochloride Enantiomer E2;-   6-{[trans-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one-dihydrochloride    Enantiomer E2;-   trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-piperidinol    dihydrochloride;-   N-trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide    hydrochloride Enantiomer E2;-   N-trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxamide    hydrochloride Enantiomer E2;-   racemic,    trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-3-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride;-   Trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-methyl-3-piperidinol    dihydrochloride;-   6-{[trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride Enantiomer E1;-   Trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-3-piperidinol    dihydrochloride;-   6-{[trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride Enantiomer E2;-   Trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-3-piperidinol    dihydrochloride;-   N-(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinamine    dihydrochloride;-   {[(1-{2-[3-Fluoro-6-(methoxy-5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-3,4-dihydro-1,8-naphthyridin-2-(1H)-one;-   7-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-2,3-dihydro-1,5-benzothiazepin-4(5H)-one;-   trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinol    dihydrochloride Enantiomer E1;-   6-{[(-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride;-   trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    Enantiomer E1;-   trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-piperidinol    dihydrochloride;-   trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride;-   trans-N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b]([1,4]thiazine-6-carboxamide    hydrochloride Enantiomer E1;-   trans-N-((3R,4R)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxamide    Isomer E1 hydrochloride;-   trans-N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxamide    Isomer E1 hydrochloride;-   6-{[trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    Enantiomer E1;-   6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride;-   6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride;-   N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinamine    dihydrochloride;-   N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)-2,3-dihydro-1,4-benzodioxin-6-sulfonamide;-   cis-6-{[(1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride Enantiomer 1;-   cis-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-3-fluoro-4-piperidinamine    dihydrochloride Enantiomer 1;-   cis-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-3-fluoro-4-piperidinamine    dihydrochloride Enantiomer 2;-   cis-6-{[(1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl-3-fluoro-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride, Enantiomer 1;-   cis-6-{[(1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride, Enantiomer 2;-   cis-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-3-fluoro-4-piperidinamine    dihydrochloride, Enantiomer 1;-   cis-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-3-fluoro-4-piperidinamine    dihydrochloride, Enantiomer 2;-   cis-6-{[(−1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride, Enantiomer 1;-   cis-6-{[(−1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride, Enantiomer 2;-   cis-N-(1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide    hydrochloride Enantiomer 1;-   6-{[((3S,4R)-1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride Enantiomer E2;-   trans-6-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]    oxazin-3-one trihydrochloride Enantiomer 1;-   trans-1-[2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinol    Enantiomer 1;-   trans-1-{2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinol    Enantiomer 2;-   2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}-1-[3-fluoro-6-(methoxy)-4-quinolinyl]ethanol    dihydrochloride Enantiomer 1;-   N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinamine;-   (3S,4R)-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinol    dihydrochloride Enantiomer 2;-   (3R,4S)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-[([1,3]oxathiolo[5,4-c]pyridin-6-ylmethyl)amino]-3-piperidinol    dihydrochloride Enantiomer E1;-   6-{[(1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one;-   1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinamine;-   (3S,4R)-1-[2-(3,6-dichloro-4-quinolinyl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinol    dihydrochloride Enantiomer E2;-   6-[({(3S,4R)-1-[2-(3,6-dichloro-4-quinolinyl)ethyl]-3-hydroxy-4-piperidinyl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride Enantiomer E2;-   (3S,4R)-1-[2-(3-chloro-6-fluoro-4-quinolinyl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinol    dihydrochloride Enantiomer E2;-   6-[({(3S,4R)-1-[2-(3-chloro-6-fluoro-4-quinolinyl)ethyl]-3-hydroxy-4-piperidinyl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride Enantiomer E2;-   N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)-2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxamide    dihydrochloride;-   N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxamide;-   N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide;-   trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-3-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride Enantiomer E1;-   trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-3-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride Enantiomer E1;-   trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-3-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride Enantiomer E2;-   trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-3-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride Enantiomer E2;-   trans-4-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-piperidinol    hydrochloride Enantiomer E1;-   trans    4-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinol    dihydrochloride Enantiomer E2;-   trans    4-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinol    dihydrochloride Enantiomer E1;-   (3S,4R)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinol    dihydrochloride Enantiomer E2;-   (3S,4R)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]-3-piperidinol    dihydrochloride Enantiomer E2;-   N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinamine    dihydrochloride;-   6-{[(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride Enantiomer E1;-   6-{[(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride Enantiomer E2;-   6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride Enantiomer E2;    6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride Enantiomer E1;-   6-{[(1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride Enantiomer E1;-   6-{[(1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dihydrochloride Enantiomer E2;-   1-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanol    dihydrochloride Enantiomer E1;-   1-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanol    dihydrochloride Enantiomer E2;-   1-[3,8-difluoro-6-(methoxy)-4-quinolinyl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanol    dihydrochloride Enantiomer E2;-   1-[3,8-difluoro-6-(methoxy)-4-quinolinyl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanol    dihydrochloride Enantiomer E1;-   1-[3-chloro-6-(methoxy)-4-quinolinyl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanol    dihydrochloride Enantiomer E2;-   1-[3-chloro-6-(methoxy)-4-quinolinyl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanol    dihydrochloride Enantiomer E1;-   1-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanol    dihydrochloride Enantiomer E2;-   2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoro-1-piperidinyl}-1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethanol    dihydrochloride Enantiomer E2;-   2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoro-1-piperidinyl}-1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethanol    dihydrochloride Enantiomer E1;-   7-{[(1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one    dihydrochloride Enantiomer E2;-   1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-N-([8-(methoxy)-2,3-dihydro-1,4-benzodioxin-6-yl]methyl}-4-piperidinamine;    and-   1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-N-[(7-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]-4-piperidinamine;    or a pharmaceutically acceptable salt thereof.

Most preferred compounds of this invention are:

-   cis-4-[(2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-1-[2-(3-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-3-ol    dihydrochloride dihydrochloride Enantiomer 1;-   (trans)-6-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]-thiazin-3-one    Dihydrochloride Enantiomer 2;-   1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinamine    dihydrochloride;-   6-{[(1-{2-[3,8-Difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one    dinydrochloride;-   N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinamine    dihydrochloride;    (3R,4S)-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinol    dihydrochloride Enantiomer 1;-   6-{[((3S,4R)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one    dihydrochloride Enantiomer 2;-   (3R,4S)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinol    dihydrochloride dihydrochloride Enantiomer 1; and-   2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl)-1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethanol    Dihydrochloride Hydrate Enantiomer 1;    or a pharmaceutically acceptable salt thereof.

Unless otherwise defined, the term (C₁₋₃)alkyl when used alone or whenforming part of other groups (such as the ‘alkoxy’ group) includessubstituted or unsubstituted, straight or branched chain alkyl groupscontaining 1 to 3 carbon atoms. Examples of (C₁₋₃)alkyl include methyl,ethyl, n-propyl, and isopropyl groups.

The term (C₂₋₄)alkenyl means a substituted or unsubstituted alkyl groupof 2 to 4 carbon atoms, wherein one carbon-carbon single bond isreplaced by a carbon-carbon double bond. Examples of (C₂₋₄)alkenylinclude ethylene, 1-propene, 2-propene, 1-butene, 2-butene, andisobutene. Both cis and trans isomers are included.

The term (C₃₋₇)cycloalkyl refers to subsituted or unsubstitutedcarbocyclic system of three to seven carbon atoms, which may contain upto two unsaturated carbon-carbon bonds. Examples of (C₃₋₇)cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, and cycloheptyl.

Unless otherwise defined, suitable substituents for any (C₁₋₃)alkyl,(C₁₋₃)alkoxy, (C₂₋₄)alkenyl, and (C₃₋₇)cycloalkyl groups includes up tothree substituents selected from the group consisting of hydroxy,halogen, nitro, cyano, carboxy, amino, amidino, sulphonamido,unsubstituted (C₁₋₃)alkoxy, trifluromethyl, and acyloxy.

Halo or halogen includes fluoro, chloro, bromo and iodo.

Haloalkyl moieties include 1-3 halogen atoms.

Unless otherwise defined, the term “heterocyclic” as used hereinincludes optionally substituted aromatic and non-aromatic, single andfused, rings suitably containing up to four hetero-atoms in each ringselected from oxygen, nitrogen and sulphur, which rings may beunsubstituted or C-substituted by, for example, up to three groupsselected from (C₁₋₄)alkylthio; halo; halo(C₁₋₄)alkoxy; halo(C₁₋₄)alkyl;(C₁₋₄)alkyl; (C₂₋₄)alkenyl; hydroxy; hydroxy(C₁₋₄)alkyl;mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; nitro; cyano, carboxy; amino oraminocarbonyl; (C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; oraminosulphonyl wherein the amino group is optionally substituted by(C₁₋₄)alkyl or (C₂₋₄)alkenyl.

Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ringatoms.

A fused heterocyclic ring system may include carbocyclic rings and needinclude only one heterocyclic ring.

Compounds within the invention containing a heterocyclyl group may occurin two or more tautometric forms depending on the nature of theheterocyclyl group; all such tautomeric forms are included within thescope of the invention.

Where an amino group forms part of a single or fused non-aromaticheterocyclic ring as defined above suitable optional substituents insuch substituted amino groups include H; trifluoromethyl; (C₁₋₄)alkyloptionally substituted by hydroxy, (C₁₋₄)alkoxy, (C₁₋₄)alkylthio,(C₂₋₄)alkenyl; halo or trifluoromethyl;

-   -   When used herein the term “aryl”, includes optionally        substituted phenyl and naphthyl.

Aryl groups may be optionally substituted with up to five, preferably upto three, groups selected from (C₁₋₄)alkylthio; halo; halo(C₁₋₄)alkoxy;halo(C₁₋₄)alkyl; (C₁₋₄)alkyl; (C₂₋₄)alkenyl; hydroxy;hydroxy(C₁₋₄)alkyl; mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; nitro; cyano;carboxy; amino or aminocarbonyl optionally substituted by (C₁₋₄)alkyl;(C₁₋₄)alkylsulphonyl; or (C₂₋₄)alkenylsulphonyl.

The term “acyl” includes formyl and (C₁₋₄)alkylcarbonyl group.

Some of the compounds of this invention may be crystallised orrecrystallised from solvents such as aqueous and organic solvents. Insuch cases solvates may be formed. This invention includes within itsscope stoichiometric solvates including hydrates as well as compoundscontaining variable amounts of water that may be produced by processessuch as lyophilisation.

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach provided in substantially pure form, for example at least 60% pure,more suitably at least 75% pure and preferably at least 85%, especiallyat least 98% pure (% are on a weight for weight basis). Impurepreparations of the compounds may be used for preparing the more pureforms used in the pharmaceutical compositions; these less purepreparations of the compounds should contain at least 1%, more suitablyat least 5% and preferably from 10 to 59% of a compound of the formula(I) or pharmaceutically acceptable derivative thereof.

Pharmaceutically acceptable derivatives of the above-mentioned compoundsof formula (I) include the free base form or their acid addition orquaternary ammonium salts, for example their salts with mineral acidse.g. hydrochloric, hydrobromic, sulphuric nitric or phosphoric acids, ororganic acids, e.g. acetic, fumaric, succinic, maleic, citric, benzoic,p-toluenesulphonic, methanesulphonic, naphthalenesulphonic acid ortartaric acids. Compounds of formula (I) may also be prepared as theN-oxide. Compounds of formula (I) having a free carboxy group may alsobe prepared as an in vivo hydrolysable ester. The invention extends toall such derivatives.

Examples of suitable pharmaceutically acceptable in vivo hydrolysableester-forming groups include those forming esters which break downreadily in the human body to leave the parent acid or its salt. Suitablegroups of this type include those of part formulae (i), (ii), (iii),(iv) and (v):

-   -   wherein R^(a) is hydrogen, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,        methyl, or phenyl, R^(b) is (C₁₋₆)alkyl, (C₁₋₆)alkoxy, phenyl,        benzyl, (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyloxy, (C₁₋₆)alkyl(C₃₋₇)        cycloalkyl, 1-amino(C₁₋₆) alkyl, or 1-(C₁₋₆alkyl)amino        (C₁₋₆)alkyl; or R^(a) and R^(b) together form a 1,2-phenylene        group optionally substituted by one or two methoxy groups; R^(c)        represents (C₁₋₆)alkylene optionally substituted with a methyl        or ethyl group and R^(d) and R^(e) independently represent        (C₁₋₆)alkyl; R^(f) represents (C₁₋₆)alkyl; R^(g) represents        hydrogen or phenyl optionally substituted by up to three groups        selected from halogen, (C₁₋₆)alkyl, or (C₁₋₆)alkoxy; Q is oxygen        or NH; R^(h) is hydrogen or (C₁₋₆)alkyl; R¹ is hydrogen,        (C₁₋₆)alkyl optionally substituted by halogen, (C₂₋₆)alkenyl,        (C₁₋₆)alkoxycarbonyl, aryl or heteroaryl; or R^(h) and R¹        together form (C₁₋₆)alkylene; R¹ represents hydrogen,        (C₁₋₆)alkyl or (C₁₋₆)alkoxycarbonyl; and R^(k) represents        (C₁₋₈)alkyl, (C₁₋₈)alkoxy, (C₁₋₆)alkoxy(C₁₋₆)alkoxy or aryl.

Examples of suitable in vivo hydrolysable ester groups include, forexample, acyloxy(C₁₋₆)alkyl groups such as acetoxymethyl,pivaloyloxymethyl, α-acetoxyethyl, α-pivaloyloxyethyl,1-(cyclohexylcarbonyloxy)prop-1-yl, and (1-aminoethyl)carbonyloxymethyl;(C₁₋₆)alkoxycarbonyloxy(C₁₋₆)alkyl groups, such asethoxycarbonyloxymethyl, α-ethoxycarbonyloxyethyl andpropoxycarbonyloxyethyl; di(C₁₋₆)alkylamino(C₁₋₆)alkyl especiallydi(C₁₋₄)alkylamino(C₁₋₄)alkyl groups such as dimethylaminomethyl,dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl;2-((C₁₋₆)alkoxycarbonyl)-2-(C₂₋₆)alkenyl groups such as2-(isobutoxycarbonyl)pent-2-enyl and 2-(ethoxycarbonyl)but-2-enyl;lactone groups such as phthalidyl and dimethoxyphthalidyl.

A further suitable pharmaceutically acceptable in vivo hydrolysableester-forming group is that of the formula:

-   -   wherein R^(k) is hydrogen, C₁₋₆alkyl or phenyl.    -   R is preferably hydrogen.

Compounds of formula (I) may also be prepared as the correspondingN-oxides.

Certain of the compounds of formula (I) may exist in the form of opticalisomers, e.g. diastereoisomers and mixtures of isomers in all ratios,e.g. racemic mixtures. The invention includes all such forms, inparticular the pure isomeric forms. For example the invention includescompound in which an A-B group CH(OH)—CH₂ is in either isomericconfiguration, the R-isomer is preferred. The different isomeric formsmay be separated or resolved one from the other by conventional methods,or any given isomer may be obtained by conventional synthetic methods orby stereospecific or asymmetric syntheses.

In a further aspect of the invention there is provided a process forpreparing compounds of formula (I), and pharmaceutically acceptablederivatives thereof, which process comprises reacting a compound offormula (IV) with a compound of formula (V):

wherein Z^(1′), R^(1′), R^(1b′), R^(1c′) and R^(3′) are Z¹, R¹, R^(1b),R^(1c) and R³ as defined in formula (I) or groups convertible thereto.

-   Q¹ is NHR^(4′) or a group convertible thereto wherein R^(4′) is R⁴    as defined in formula (I) or groups convertible thereto and Q² is H    or R^(3′) or Q¹ and Q² together form an optionally protected oxo    group;-   (i) X is A′-COW, Y is H;-   (ii) X is CH═CH₂, Y is H;-   (iii) X is oxirane, Y is H;-   (iv) one of X and Y is CO₂R^(y) and the other is CH₂CO₂R^(x);    in which W is a leaving group, e.g. halo or imidazolyl; R^(x) and    R^(y) are (C₁₋₄)alkyl; A′ is A as defined in formula (I), or groups    convertible thereto; and oxirane is:    and thereafter optionally or as necessary converting Q¹ and Q² to    NHR^(4′); converting A′, Z^(1′), R^(1′), R^(1b′), R^(1c′), R^(3′),    and R^(4′) to A, Z¹, R¹, R^(1b), R^(1c), R³, and R⁴; converting A-B    to other A-B, interconverting R¹, R^(1b), R^(1c), R³, and/or R⁴,    and/or forming a pharmaceutically acceptable derivative thereof.

Process variant (i) initially produces compounds of formula (I) whereinA-B is A′-CO.

Process variant (ii) initially produces compounds of formula (I) whereinA-B is CH₂CH₂.

Process variant (iii) initially produces compounds of formula (I)wherein A-B is CH(OH)—CH₂.

Process variant (iv) initially produces compounds of formula (I) whereinA-B is CO—CH₂ or CH₂—CO.

In process variant (i) the reaction is a standard amide formationreaction involving e.g.:

-   1. Activation of a carboxylic acid (e.g. to an acid chloride, mixed    anhydride, active ester, O-acyl-isourea or other species), and    treatment with an amine (Ogliaruso, M. A.; Wolfe, J. F. in The    Chemistry of Functional Groups (Ed. Patai, S.) Suppl. B: The    Chemistry of Acid Derivatives, Pt. 1 (John Wiley and Sons, 1979), pp    442-8; Beckwith, A. L. J. in The Chemistry of Functional Groups (Ed.    Patai, S.) Suppl. B: The Chemistry of Amides (Ed. Zabricky, J.)    (John Wiley and Sons, 1970), p 73 ff. The acid and amine are    preferably reacted in the presence of an activating agent such as    1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or    1-hydroxybenzotriazole (HOBT) or    O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate (HATU); or-   in situ conversion of the acid component into the acid chloride    under neutral conditions (Villeneuve, G. B.; Chan, T. H.,    Tetrahedron. Lett. 1997, 38, 6489).

A′ may be, for example, protected hydroxymethylene.

The process variant (ii) is a standard addition reaction using methodswell known to those skilled in the art. The process is preferablycarried out in a polar organic solvent e.g. acetonitrile, DMF orchloroform optionally in the presence of an organic base e.g.triethylamine. In some cases an elevated temperature such as 40-150° C.may be beneficial.

In process variant (iii) the coupling may be effected in the absence ofsolvent, or in a suitable solvent such as acetonitrile, chloroform ordimethylformamide at room temperature optionally in the presence of oneequivalent of lithium perchlorate as catalyst (general method of J. E.Chateauneuf et al, J. Org. Chem., 56, 5939-5942, 1991) or with ytterbiumtriflate in dichloromethane. In some cases an elevated temperature suchas 40-70° C. may be beneficial. Alternatively, the piperidine may betreated with a base, such as one equivalent of butyl lithium, and theresulting salt reacted with the oxirane in an inert solvent such astetrahydrofuran, preferably at an elevated temperature such as 80° C.Use of a chiral epoxide will afford single diastereomers. Alternatively,mixtures of diastereomers may be separated by preparative HPLC or byconventional resolution through crystallisation of salts formed fromchiral acids.

In process variant (iv) the process is two step: firstly a condensationusing a base, preferably sodium hydride or alkoxide, sodamide, alkyllithium or lithium dialkylamide, preferably in an aprotic solvent e.g.ether, THF or benzene; secondly, hydrolysis using an inorganic acid,preferably HCl in aqueous organic solvent at 0-100° C. Analogous routesare described in DE330945, EP31753, EP53964 and H. Sargent, J. Am. Chem.Soc. 68, 2688-2692 (1946). Similar Claisen methodology is described inSoszko et. al., Pr. Kom. Mat. Przyr. Poznan. Tow. Przyj. Nauk., (1962),10, 15.

Reduction of a carbonyl group of A or B to CHOH can be readilyaccomplished using reducing agents well known to those skilled in theart, e.g. sodium borohydride in aqueous ethanol or methanol, or lithiumaluminium hydride in ethereal solution. This is analogous to methodsdescribed in EP53964, U.S. Pat. No. 384,556 and J. Gutzwiller et al, J.Amer. Chem. Soc., 1978, 100, 576.

The carbonyl group of A or B may be reduced to CH₂ by treatment with areducing agent such as hydrazine in ethylene glycol, at e.g. 130-160°C., in the presence of potassium hydroxide.

A hydroxy group on A or B may be oxidised to a carbonyl group byoxidants well known to those skilled in the art, for example, manganesedioxide, pyridinium chlorochromate or pyridinium dichromate.

A hydroxyalkyl A-B group CHR⁶CHOH or CR⁶(OH)CH₂ may be dehydrated togive the group CR⁶═CH by treatment with an acid anhydride such as aceticanhydride.

Methods for conversion of CH═CH by reduction to CH₂CH₂ are well known tothose skilled in the art, for example using hydrogenation over palladiumon carbon as catalyst. Methods for conversion of CR⁶═CH to give the A-Bgroup CR⁶(OH)CH₂ are well known to those skilled in the art for exampleby epoxidation and subsequent reduction by metal hydrides.

An amide carbonyl group may be reduced to the corresponding amine usinga reducing agent such as lithium aluminium hydride.

A hydroxy group in A or B may be converted to azido by activation anddisplacement e.g. under Mitsunobu conditions using hydrazoic acid or bytreatment with diphenylphosphorylazide and base, and the azido group inturn may be reduced to amino by hydrogenation.

When Q¹ Q² together form a protected oxo group this may be an acetalsuch as ethylenedioxy which can subsequently be removed by acidtreatment to give a compound of formula (VI):

wherein the variables are as described for formula (I).

The ketone of formula (VI) is reacted with an amine HNH′R^(4′) byconventional reductive alkylation using, e.g., sodium borohydride orsodium triacetoxyborohydride (Gribble, G. W. in Encyclopedia of Reagentsfor Organic Synthesis (Ed. Paquette, L. A.) (John Wiley and Sons, 1995),p 4649).

Examples of groups Z^(1′) convertible to Z¹, include CR^(1a) whereR^(1a′) is a group convertible to R^(1a), R^(1a′), R^(1′), R^(1b′) andR^(1c′) are preferably R^(1a), R¹, R^(1b), and R^(1c). R^(3′) is R³ or agroup convertible thereto. R^(4′) is R⁴ or more preferably H or anN-protecting group such as t-butoxycarbonyl, benzyloxycarbonyl or9-fluorenylmethoxycarbonyl. R^(1b) is preferably H or F. R^(1c) ispreferably Cl or F.

Conversions of R^(1′), R^(1b′), R^(1c′), R^(3′) and R^(4′) andinterconversions of R¹, R^(1b), R^(1c), R³ and R⁴ are conventional. Incompounds which contain an optionally protected hydroxy group, suitableconventional hydroxy protecting groups which may be removed withoutdisrupting the remainder of the molecule include acyl and alkylsilylgroups. N-protecting groups are removed by conventional methods.

For example R^(1′) or R^(1a′) methoxy is convertible to R¹ or R^(1a)hydroxy by treatment with HBr or lithium and diphenylphosphine (generalmethod described in Ireland et al, J. Amer. Chem. Soc., 1973, 7829) orHBr. Alkylation of the hydroxy group with a suitable (C₁₋₄)alkyl or(C₁₋₄)alkoxy derivative bearing a leaving group such as halide willproduce R^(1′) is (C₁₋₄)alkoxy or R^(1a) is (C₁₋₄)alkoxy substituted by(C₁₋₄)alkoxy. R^(3′) alkenyl is convertible to hydroxyalkyl byhydroboration using a suitable reagent such as9-borabicyclo[3.3.1]nonane, epoxidation and reduction or oxymercuration.

Carboxy groups within R³ may be prepared by Jones' oxidation of thecorresponding alcohols CH₂OH using chromium acid and sulphuric acid inwater/methanol (E. R. H. Jones et al, J. Chem. Soc., 1946, 39). Otheroxidising agents may be used for this transformation such as sodiumperiodate catalysed by ruthenium trichloride (G. F. Tutwiler et al, J.Med. Chem., 1987, 30(6), 1094), chromium trioxide-pyridine (G. Just etal, Synth. Commun., 1979, 9(7), 613), potassium permanganate (D. E.Reedich et al, J. Org. Chem., 1985, 50(19), 3535), and pyridiniumchlorochromate (D. Askin et al, Tetrahedron Lett., 1988, 29(3), 277).

The carboxy group may alternatively be formed in a two stage process,with an initial oxidation of the alcohol to the corresponding aldehydeusing for instance dimethyl sulphoxide activated with oxalyl chloride(N. Cohen et al, J. Am. Chem. Soc., 1983, 105, 3661)ordicyclohexylcarbodiimide (R. M. Wengler, Angew. Chim. Int. Ed. Eng.,1985, 24(2), 77), or oxidation with tetrapropylammonium perruthenate(Ley et al, J. Chem. Soc. Chem Commun., 1987, 1625). The aldehyde maythen be separately oxidised to the corresponding acid using oxidisingagents such as silver (II) oxide (R. Grigg et al, J. Chem. Soc. Perkin1,1983, 1929), potassium permanganate (A. Zurcher, Helv. Chim. Acta.,1987, 70 (7), 1937), sodium periodate catalysed by ruthenium trichloride(T. Sakata et al., Bull. Chem. Soc. Jpn., 1988, 61(6), 2025), pyridiniumchlorochromate (R. S. Reddy et al, Synth. Commun., 1988, 18(51), 545) orchromium trioxide (R. M. Coates et al, J. Am. Chem. Soc., 1982, 104,2198).

Other routes to the synthesis of carboxy groups within R³ are well knownto those skilled in the art.

R³ groups containing a carboxy group may also be prepared by conversionof an alcohol to a suitable leaving group such as the correspondingtosylate by reaction with para-toluenesulphonyl chloride (M. R. Bell, J.Med. Chem., 1970, 13, 389), or the iodide using triphenylphosphine,iodine, and imidazole (G. Lange, Synth. Commun., 1990, 20, 1473). Thesecond stage is the displacement of the leaving group with cyanide anion(L. A. Paquette et al, J. Org. Chem., 1979, 44(25), 4603; P. A. Griecoet al, J. Org. Chem., 1988, 53(16), 3658. Finally acidic hydrolysis ofthe nitrile group gives the desired acids (H. Rosemeyer et al,Heterocycles, 1985, 23 (10), 2669). The hydrolysis may also be carriedout with base e.g. potassium hydroxide (H. Rapoport, J. Org. Chem.,1958, 23, 248) or enzymatically (T. Beard et al, Tetrahedron Asymmetry,1993, 4 (6), 1085).

R³ cis or trans hydroxy may be introduced by the methods of van Deale etal., Drug Development Research 8:225-232 (1986) or Heterocycles 39(1),163-170 (1994). For trans hydroxy, a suitable method convertsN-protected tetrahydropyridine to the epoxide by treatment withmetachloroperbenzoic acid, followed by opening of the epoxide with asuitable amine NR^(2′)R^(4′).

Other functional groups in R³ may be obtained by conventionalconversions of hydroxy, carboxy or cyano groups.

Other substituents on R³ alkyl or alkenyl may be interconverted byconventional methods, for example hydroxy may be derivatised byetherification. Primary and secondary hydroxy groups can be oxidised toan aldehyde or ketone respectively and alkylated with a suitable agentsuch as an organometallic reagent to give a secondary or tertiaryalcohol as appropriate. A carboxylate group may be converted to anhydroxymethyl group by reduction of an ester of this acid with asuitable reducing agent such as lithium aluminium hydride.

An NH₂ substituent on piperidine is converted to NHR⁴ by conventionalmeans such as amide or sulphonamide formation with an acyl derivativeR⁵COW or R⁵SO₂W, for compounds where U is CO or SO₂ or, where U is CH₂,by alkylation with an alkyl halide R⁵CH₂-halide in the presence of base,acylation/reduction with an acyl derivative R⁵COW or reductivealkylation with an aldehyde R⁵CHO.

Where one of R³ or R⁶ contains a carboxy group and the other contains ahydroxy or amino group they may together form a cyclic ester or amidelinkage. This linkage may form spontaneously during coupling of thecompound of formula (IV) and the piperidine moiety or in the presence ofstandard peptide coupling agents.

It will be appreciated that under certain circumstances interconvertionsmay interfere, for example, A or B hydroxy groups in A or B and thepiperidine substituent NH₂ will require protection e.g. as a carboxy- orsilyl-ester group for hydroxy and as an acyl derivative for piperidineNH₂, during conversion of R^(1′), R^(3′) or R⁴, or during the couplingof the compounds of formulae (IV) and (V).

Compounds of formulae (IV) and (V) are known compounds, (see for exampleSmith et al, J. Amer. Chem. Soc., 1946, 68, 1301) or preparedanalogously.

4-Alkenyl compounds of formula (IV) may be prepared by conventionalprocedures from a corresponding 4-halogeno-derivative by e.g. a Hecksynthesis as described in e.g. Organic Reactions, 1982, 27, 345 or via2,4,6-trivinylcyclotroboroxane (J. Org. Chem. 2002, 67, 4968-4971).

4-Halogeno derivatives of compounds of formula (IV) are commerciallyavailable, or may be prepared by methods known to those skilled in theart. For example, a 4-chloroquinoline is prepared from the correspondingquinolin-4-one by reaction with phosphorus oxychloride (POCl₃) orphosphorus pentachloride, PCl₅ and 4-bromoquinoline is preparedsimilarly with phosphorous oxybromide or more preferably phosphoroustribromide in N,N-dimethylformamide (see M. Schmittel et al, Synlett,1997, (9), 1096 and K. Gould et al, J. Med., Chem., 1988, 31 (7), 1445).4-Carboxy derivatives of compounds of formula (IV) are commerciallyavailable or may be prepared by conventional procedures for preparationof carboxy heteroaromatics well known to those skilled in the art.

A 4-oxirane derivative of compounds of formula (IV) is convenientlyprepared from the 4-carboxylic acid by first conversion to the acidchloride with oxalyl chloride and then reaction withtrimethylsilyldiazomethane to give the diazoketone derivative.Subsequent reaction with 5M hydrochloric acid gives thechloromethylketone. Reduction with sodium borohydride in aqueousmethanol gives the chlorohydrin which undergoes ring closure to affordthe epoxide on treatment with base, e.g. potassium hydroxide inethanol-tetrahydrofuran.

Alternatively and preferably, 4-oxirane derivatives can be prepared frombromomethyl ketones which can be obtained from 4-hydroxy compounds byother routes well known to those skilled in the art. For example,hydroxy compounds can be converted to the corresponding4-trifluoromethanesulphonates by reaction with trifluoromethanesulphonicanhydride under standard conditions (see K. Ritter, Synthesis, 1993,735). Conversion into the corresponding butyloxyvinyl ethers can beachieved by a Heck reaction with butyl vinyl ether under palladiumcatalysis according to the procedure of W. Cabri et al, J. Org. Chem,1992, 57 (5), 1481. (Alternatively, the same intermediates can beattained by Stille coupling of the trifluoromethanesulphonates or theanalaogous chloro derivatives with (1-ethoxyvinyl)tributyl tin, T. R.Kelly, J. Org. Chem., 1996, 61, 4623.) The alkyloxyvinyl ethers are thenconverted into the corresponding bromomethylketones by treatment withN-bromosuccinimide in aqueous tetrahydrofuran in a similar manner to theprocedures of J. F. W. Keana, J. Org. Chem., 1983, 48, 3621 and T. R.Kelly, J. Org. Chem., 1996, 61, 4623.

The 4-hydroxyderivatives can be prepared from an aminoaromatic byreaction with methylpropiolate and subsequent cyclisation, analogous tothe method described in N. E. Heindel et al, J. Het. Chem., 1969, 6, 77.For example, 5-amino-2-methoxy pyridine can be converted to4-hydroxy-6-methoxy-[1,5]naphthyridine using this method.

If a chiral reducing agent such as (+) or(−)-B-chlorodiisopinocamphenylborane [‘DIP-chloride’] is substituted forsodium borohydride, the prochiral chloromethylketone may be convertedinto the chiral chlorohydrin [see C. Bolm et al, Chem. Ber. 125,1169-1190, (1992)].

Recrystallisation of the chiral epoxide or chiral HPLC gives materialwith enhanced optical purity (typically ee >95%).

The chiral )-epoxide, when reacted with a piperidine derivative givesethanolamine compounds as single diastereomers with -correspondingchiral stereochemistry at the benzylic position.

Alternatively, the chiral epoxide can be prepared from the 4-vinylderivative by an osmium-catalysed asymmetric dihydroxylation usingeither AD-mix-β or AD-mix-α (see K. B. Sharpless et al. J. Org. Chem.1992, 57, 2768-2771) giving chiral diols, (typically ee values of 40-65%for 3-fluoro-naphthyridines/quinolines) which can be converted to themono-tosyl-derivative by reaction with tosyl chloride (DCM-THF-Et₃N)(conveniently catalysed by dibutyltinoxide—see M. J. Martinelli et al.J.A.C.S. 2002, 124, 3578-3585), followed by reaction with a base such asanhydrous potassium carbonate in methanol.

Alternatively, the epoxide may be prepared from the 4-carboxaldehyde bya Wittig approach using trimethylsulfonium iodide [see G. A. Epling andK-Y Lin, J. Het. Chem., 1987, 24, 853-857], or by epoxidation of a4-vinyl derivative. 4-Hydroxy-1,5-naphthyridines can be prepared from3-aminopyridine derivatives by reaction with diethyl ethoxymethylenemalonate to produce the 4-hydroxy-3-carboxylic acid ester derivativewith subsequent hydrolysis to the acid, followed by thermaldecarboxylation in quinoline (as for example described for4-Hydroxy-[1,5]naphthyridine-3-carboxylic acid, J. T. Adams et al., J.Amer. Chem. Soc., 1946, 68, 1317).

Compounds of formula (IV) are available by the sequence described below,starting from an aromatic or heterocyclic amine (1), with at least onefree CH position adjacent to the amine. Reaction with Meldrum's acid andtrimethyl orthformate in ethanol at reflux affords the corresponding2,2-dimethyl-5-phenylaminomethylene-[1,3]dioxane-4,6-dione derivatives(2). These can be cyclised at elavated temperatures (180-220° C.) ininert solvents such as Dowtherm to give the corresponding1H-quinolin-4-one or heterocyclic derivatives (3). These processes arewell-established and are described by Walz and Sundberg (J. Org. Chem.,2000, 65 (23), 8001) and by Todter and Lackner (Synthesis, 1997 (5)576).

A 4-hydroxy-[1,5]naphthyridine can be converted to the 4-chloroderivative by heating in phosphorus oxychloride, or to the4-methanesulphonyloxy or 4-trifluoromethanesulphonyloxy derivative byreaction with methanesulphonyl chloride or trifluoromethanesulphonicanhydride, respectively, in the presence of an organic base. Activationof the quinolone species related to (3) into the corresponding4-quinolyl bromides (4) can be accomplished with phosphorous oxybromideor more preferably phosphorous tribromide in N,N-dimethylformamide (seeM. Schmittel et al, Synlett, 1997, (9), 1096 and K. Gould et al, J.Med., Chem., 1988, 31 (7), 1445). The corresponding chlorides (5) areavailable by using phosphoryl oxychloride (for instance C. W. Wright etal, J. Med., Chem., 2001, 44 (19), 3187).

Alternatively, the quinolone species may be activated to thecorresponding 1,1,1-trifluoro-methanesulfonic acid quinolin-4-yl esters(6) by the action of agents such as triflic anhydride or more preferablyN-trifluoromethanesulphonimide (see for example M. Alvarez et al, Tet2000, 56 (23) 3703; M. Alvarez et al, Eur. J. Org., Chem., 2000, (5),849; J. Joule et al, Tet, 1998, 54 (17), 4405; J. K. Stille et al,J.A.C.S., 1988, 110 (12), 4051).

1,5-Naphthyridines may be prepared by other methods well known to thoseskilled in the art (for examples see P. A. Lowe in “ComprehensiveHeterocyclic Chemistry” Volume 2, p 581-627, Ed A. R. Katritzky and C.W. Rees, Pergamon Press, Oxford, 1984).

3-Chloro-4-hydroxyquinolines or naphthyridines may be prepared bychlorination of the 4-hydroxyquinoline or naphthyridine with a suitablereagent eg. N-chlorosuccinimide in acetic acid. The 4-hydroxy group maythen be converted into the trifluoromethylsulfonate ester by treatmentwith a sulfonation reagent eg. N-phenyltrifluoromethanesulfonimide, orinto the 4-bromo compound by treatment with phosphorus tribromide indimethylformamide.

3-bromo-4-hydroxyquinolines or naphthyridines may be prepared, in asimilar mannar as given above, by bromination of the 4-hydroxyquinolineor naphthyridine with a suitable reagent eg. N-bromosuccinimide inacetic acid. The 4-hydroxy group may then be converted into thetrifluoromethylsulfonate ester by treatment with a sulfonation reagenteg. N-phenyltrifluoromethanesulfonimide, or into the 4-bromo compound bytreatment with phosphorus tribromide in dimethylformamide.

3-Fluoro-4-chloroquinolines may be prepared from the 3-amino-4-chlorocompounds by conversion into the diazonium tetrafluoroborate salt, usingsodium nitrite and tetrafluoroboric acid or nitrosoniumtetrafluoroborate in a suitable solvent (EP 430,434), followed bythermal decomposition (WO 98/13350 and WO 02/072578). The 3-aminocompounds may be prepared either from the 3-carboxylic acid by heatingwith diphenylphosphoryl azide in the presence of triethylamine andtert-butanol, followed by deprotection of the resulting tert-butylcarbamate with acid (WO 02/072578), or from the 3-nitro compound byreduction, for example with hydrogen in the presence of Raney nickel (WO98/13350).

For compounds of formula (V), suitable amines may be prepared from thecorresponding 4-substituted piperidine acid or alcohol. In a firstinstance, an N-protected piperidine containing an acid bearingsubstituent, can undergo a Curtius rearrangement and the intermediateisocyanate can be converted to a carbamate by reaction with an alcohol.Conversion to the amine may be achieved by standard methods well knownto those skilled in the art used for amine protecting group removal. Forexample, an acid substituted N-protected piperidine can undergo aCurtius rearrangement e.g. on treatment with diphenylphosphoryl azideand heating, and the intermediate isocyanate reacts in the presence of2-trimethylsilylethanol to give the trimethylsilylethylcarbamate (T. L.Capson & C. D. Poulter, Tetrahedron Lett., 1984, 25, 3515). Thisundergoes cleavage on treatment with tetrabutylammonium fluoride to givethe 4-amine substituted N-protected piperidine.

In a second instance, an N-protected piperidine containing an alcoholbearing substituent undergoes a Mitsunobu reaction (for example asreviewed in Mitsunobu, Synthesis, (1981), 1), for example withsuccinimide in the presence of diethyl azodicarboxylate andtriphenylphosphine to give the phthalimidoethylpiperidine. Removal ofthe phthaloyl group, for example by treatment with methylhydrazine,gives the amine of formula (V).

R⁵CH₂-halides, acyl derivative R⁵COW and R⁵SO₂W or aldehydes R⁵CHO arecommercially available or are prepared conventionally. The aldehydes maybe prepared by partial reduction of the R⁵-ester with lithium aluminiumhydride or di-isobutylaluminium hydride or more preferably by reductionto the alcohol, with lithium aluminium hydride or sodium borohydride orlithium triethylborohydride (see Reductions by the Alumino- andBorohydrides in Organic Synthesis, 2nd ed., Wiley, N.Y., 1997; JOC,3197, 1984; Org. Synth. Coll., 102, 1990; 136, 1998; JOC, 4260, 1990;TL, 995, 1988; JOC, 1721, 1999; Liebigs Ann./Recl., 2385, 1997; JOC,5486, 1987), followed by oxidation to the aldehyde with manganese (II)dioxide. The aldehydes may also be prepared from carboxylic acids in twostages by conversion to a mixed carbonate for example by reaction withisobutyl chloroformate followed by reduction with sodium borohydride (R.J. Alabaster et al., Synthesis, 598, 1989) to give the hydroxymethylsubstituted heteroaromatic or aromatic and then oxidation with astandard oxidising agent such as pyridinium dichromate or manganese (II)dioxide. Acyl derivative R⁵COW may be prepared by activation of theR⁵-ester. R⁵CH₂-halides such as bromides may be prepared from thealcohol R⁵CH₂OH by reaction with phosphorus tribromide inDCM/triethylamine.

Alternatively the aldehyde R⁵CHO and sulphonic acid derivative R⁵SO₂Wmay be generated by treatment of the R⁵H heterocycle with suitablereagents. For example benzoxazinones, or more preferably theirN-methylated derivatives can be formylated with hexamine in eithertrifluoroacetic acid or methanesulfonic acid, in a modified Duffprocedure [O. I. Petrov et al. Collect. Czech. Chem. Commun. 62, 494-497(1997)]. 4-Methyl-4H-benzo[1,4]oxazin-3-one may also be formylated usingdichloromethyl methyl ether and aluminium chloride giving exclusivelythe 6-formyl derivative. Reaction of a R⁵H heterocycle withchlorosulphonic acid gives the sulphonic acid derivative (by methodsanalogous to Techer et. al., C. R. Hebd. Seances Acad. Sci. Ser. C; 270,1601, 1970).

The aldehyde R⁵CHO may be generated by conversion of an R⁵ halogen or R⁵trifluoromethane sulphonyloxy derivative into an olefin with subsequentoxidative cleavage by standard methods. For example, reaction of a bromoderivative under palladium catalysis with trans-2-phenylboronic acidunder palladium catalysis affords a styrene derivative which uponozonolysis affords the required R⁵CHO (Stephenson, G. R., Adv.Asymmetric Synth. (1996), 275-298. Publisher: Chapman & Hall, London).

R⁵ heterocycles are commercially available or may be prepared byconventional methods. For example where a benzoxazinone is required, anitrophenol may be alkylated with for example ethyl bromoacetate and theresulting nitro ester reduced with Fe in acetic acid (alternativelyZn/AcOH/HCl or H₂ Pd/C or H₂ Raney Ni). The resulting amine will undergospontaneous cyclisation to the required benzoxazinone. Alternatively anitrophenol may be reduced to the aminophenol, which is reacted withchloroacetyl chloride [method of X. Huang and C. Chan, Synthesis 851(1994)] or ethyl bromoacetate in DMSO [method of Z. Moussavi et al. Eur.J. Med. Chim. Ther. 24, 55-60 (1989)]. The same general routes can beapplied to prepare benzothiazinones [See for example F. Eiden and F.Meinel, Arch. Pharm. 312, 302-312 (1979), H. Fenner and R GrauertLiebigs. Ann. Chem. 193-313 (1978)]]. A variety of routes are availableto prepare aza analogues of benzothiazinones via the key correspondingaldehydes. For instance,2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazine-7-carbaldehyde may beaccessed from 5-fluoro-2-picoline (E. J. Blanz, F. A. French, J. R.DoAmaral and D. A. French, J. Med. Chem. 1970, 13, 1124-1130) byconstructing the thiazinone ring onto the pyridyl ring thenfunctionalising the methyl substituent. The dioxin analogue of this azasubstitution patern,2,3-dihydro-[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde is accessiblefrom Kojic acid by aminolysis from pyrone to pyridone then annelatingthe dioxin ring. Other aza substitution patterns withpyridothiazin-3-one, pyridooxazin-3-one, and pyridodioxin ring systemsare also accessible. Ortho-aminothiophenols may be conveniently preparedand reacted as their zinc complexes [see for example V. Taneja et alChem. Ind. 187 (1984)]. Benzoxazolones may be prepared from thecorresponding aminophenol by reaction with carbonyl diimidazole,phosgene ot triphosgene. Reaction of benzoxazolones with diphosporuspentasulfide affords the corresponding 2-thione. Thiazines and oxazinescan be prepared by reduction of the corresponding thiazinone oroxazinone with a reducing agent such as lithium aluminium hydride.

The amines R^(4′)NH₂ are available commercially or preparedconventionally. For example amines R⁵CH₂NH₂ may be prepared from abromomethyl derivative by reaction with sodium azide indimethylformamide (DMF), followed by hydrogenation of the azidomethylderivative over palladium-carbon. An alternative method is to usepotassium phthalimide/DMF to give the phthalimidomethyl derivative,followed by reaction with hydrazine in DCM to liberate the primaryamine.

Conversions of R^(1a′), R^(1b′), R^(1c′), R^(3′) and R^(4′) may becarried out on the intermediates of formulae (IV), and (V) prior totheir reaction to produce compounds of formula (I) in the same way asdescribed above for conversions after their reaction.

Another method of synthesizing compound of formula (I) is outlined inScheme I.

Allylic alcohol (I-I) can be prepared by procedures outlined in eitherHeterocycles 1992, 33, 349 or Synthesis 2000, 521, 33, 349. Oxidation of(I-I) with MCPBA cleanly affords cis epoxide (I-II). Treatment of (I-II)with NaN₃ in DMF containing LiClO₄ at elevated temperatures affords amixture of dihydroxy azides with isomer (I-III) predominating. Theisomers can be easily separated by column chromatography and thestructure of (I-III) confirmed by COSY NMR. Conversion of (I-III) totarget compounds such as (I-IV) can be accomplished using the sameprocedures used to prepare the mono-hydroxy derivatives describedherein.

Further details for the preparation of compounds of formula (I) arefound in the examples.

The compounds of formula (I) may be prepared singly or as compoundlibraries comprising at least 2, for example 5 to 1,000 compounds, andmore preferably 10 to 100 compounds of formula (I). Libraries ofcompounds of formula (I) may be prepared by a combinatorial “split andmix” approach or by multiple parallel synthesis using either solutionphase or solid phase chemistry, by procedures known to those skilled inthe art.

Thus according to a further aspect of the invention there is provided acompound library comprising at least 2 compounds of formula (I) orpharmaceutically acceptable derivatives thereof.

Novel intermediates of formulae (IV) and (V) are also part of thisinvention.

The antibacterial compounds according to the invention may be formulatedfor administration in any convenient way for use in human or veterinarymedicine, by analogy with other antibacterials.

The pharmaceutical compositions of the invention include those in a formadapted for oral, topical or parenteral use and may be used for thetreatment of bacterial infection in mammals including humans.

The composition may be formulated for administration by any route. Thecompositions may be in the form of tablets, capsules, powders, granules,lozenges, creams or liquid preparations, such as oral or sterileparenteral solutions or suspensions.

The topical formulations of the present invention may be presented as,for instance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present as from about 1% up to about 98% of theformulation. More usually they will form up to about 80% of theformulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrrolidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g.cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilisedbefore filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilized powder is thensealed in the vial and an accompanying vial of water for injection maybe supplied to reconstitute the liquid prior to use. Parenteralsuspensions are prepared in substantially the same manner except thatthe compound is suspended in the vehicle instead of being dissolved andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% by weight, preferably from 10-60%by weight, of the active material, depending on the method ofadministration. Where the compositions comprise dosage units, each unitwill preferably contain from 50-500 mg of the active ingredient. Thedosage as employed for adult human treatment will preferably range from100 to 3000 mg per day, for instance 1500 mg per day depending on theroute and frequency of administration. Such a dosage corresponds to 1.5to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.

No toxicological effects are indicated when a compound of formula (I) ora pharmaceutically acceptable derivative thereof is administered in theabove-mentioned dosage range.

The compound of formula (I) may be the sole therapeutic agent in thecompositions of the invention or a combination with otherantibacterials. If the other antibacterial is α-lactam then aβ-lactamase inhibitor may also be employed.

Compounds of formula (I) are active against a wide range of organismsincluding both Gram-negative and Gram-positive organisms.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following examples illustrate the preparation of certain compoundsof formula (I) and the activity of certain compounds of formula (I)against various bacterial organisms.

Abbreviations in the examples:

-   RT=room temperature-   ES=Electrospray mass spec.-   LCMS=Liquid chromatography mass spec.-   APCl+=Atmospheric pressure chemical ionisation mass spec.

Certain reagents are also abbreviated herein. DCC refers todicyclohexylcarbodiimide, DMAP refers to dimethylaminopyridine, DIEArefers to diisopropylethyl amine, EDC refers to1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride. HOBtrefers to 1-hydroxybenzotriazole, THF refers to tetrahydrofuran, DIEArefers to diisopropylethylamine, DEAD refers to diethylazodicarboxylate, PPh₃ refers to triphenylphosphine, DIAD refers todiisopropyl azodicarboxylate, DME refers to dimethoxyethane, DMF refersto dimethylformamide, NBS refers to N-bromosuccinimide, Pd/C refers to apalladium on carbon catalyst, PPA refers to polyphosphoric acid, DPPArefers to diphenylphosphoryl azide, BOP refers tobenzotriazol-1-yloxy-tris(dimethyl-amino)phosphoniumhexafluorophosphate, HF refers to hydrofluoric acid, TEA refers totriethylamine, TFA refers to trifluoroacetic acid, PCC refers topyridinium chlorochromate.

EXAMPLES AND EXPERIMENTAL General

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded at 300MHz, and chemical shifts are reported in parts per million (δ) downfieldfrom the internal standard tetramethylsilane (TMS). Abbreviations forNMR data are as follows: s=singlet, d=doublet, t=triplet, q=quartet,m=multiplet, dd=doublet of doublets, dt=doublet of triplets,app=apparent, br=broad. J indicates the NMR coupling constant measuredin Hertz. CDCl₃ is deuteriochloroform, DMSO-d₆ ishexadeuteriodimethylsulfoxide, and CD₃OD is tetradeuteriomethanol. Massspectra were obtained using electrospray (ES) ionization techniques.Elemental analyses were performed by Quantitative Technologies Inc.,Whitehouse, N.J. Melting points were obtained on a Thomas-Hoover meltingpoint apparatus and are uncorrected. All temperatures are reported indegrees Celsius. E. Merck Silica Gel 60 F-254 thin layer plates wereused for thin layer chromatography. Flash chromatography was carried outon E. Merck Kieselgel 60 (230-400 mesh) silica gel. Analytical HPLC wasperformed on Beckman chromatography systems. Preparative HPLC wasperformed using Gilson chromatography systems. ODS refers to anoctadecylsilyl derivatized silica gel chromatographic support. YMCODS-AQ® is an ODS chromatographic support and is a registered trademarkof YMC Co. Ltd., Kyoto, Japan. PRP-1® is a polymeric(styrene-divinylbenzene) chromatographic support, and is a registeredtrademark of Hamilton Co., Reno, Nev. Celite® is a filter aid composedof acid-washed diatomaceous silica, and is a registered trademark ofManville Corp., Denver, Colo.

Example 16-({1-[(Racemic)-2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2hydroxy-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-oneDihydrochloride (a) 3-Chloro-6-methoxy-[1,5]naphthyridin-4-ol

6-Methoxy-[1,5]naphthyridin-4-ol (12 g) in acetic acid (200 mL) wassonicated and warmed until all had dissolved, and then it was treatedwith N-chlorosuccinimide (10.01 g) and the mixture was heated at 35° C.for 18 hr, cooled, and the solid collected and washed with acetic acidand dried in vacuo at 40° C. overnight, to give a white solid (9.5 g).

MS (ES) m/z 211/213 (M+H)⁺.

(b) 1,1,1-Trifluoro-methanesulfonic acid3-chloro-6-methoxy-[1,5]naphthyridin-4-yl ester

A suspension of 60% sodium hydride in oil (3.08 g) was washed withhexane, the hexane solution decanted, and dry DMF (200 mL) addedfollowed by the phenol (1a) (11.62 g). The mixture was stirred at roomtemperature for 1 hr, cooled in ice,N-phenyltrifluoromethanesulphonimide (21.62 g) added and the mixture wasallowed to stir at room temperature overnight. It was evaporated,azeotroped with toluene, taken up in ether-DCM and washed with sodiumcarbonate solution, dried (sodium sulfate) and evaporated to give asolid (15 g).

MS (+ve ion electrospray) m/z 343/345 (MH+).

(c) 8-(1-Butoxy-vinyl)-7-chloro-2-methoxy-[1,5]naphthyridine

The triflate (1b) (8.8 g) in DMF (80 mL) with triethylamine (7.2 mL)butyl vinyl ether (19.3 mL), palladium (II) acetate (0.584 g) and1,3-bis(diphenylphosphino)propane (1.06 g) was heated at 65-70° C. for30 hours then evaporated, azeotroped with toluene, and chromatographedon silica gel (dichloromethane-hexane) to give a solid (3.7 g).

MS (ES) m/z 293/295 (M+H)⁺.

(d) 2-Bromo-1-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethanone

The vinyl ether (1c) (6.51 g) was dissolved in THF (100 mL), and water(9 mL) and treated with N-bromosuccinimide (6.51 g) for 5 hour, thenevaporated and chromatographed on silica gel (dichloromethane-hexane) togive the ketone as a solid (8.9 g).

MS (ES) m/z 315/317 (M+H)⁺.

(e) 7-Chloro-2-methoxy-8-(R/S)-oxiranyl-[1,5]naphthyridine

The ketone (1d) (10.5 g) in methanol (160 mL) and water (40 mL) wascooled in ice and sodium borohydride (2.59 g) was added and the solutionstirred at room temperature for 1.5 hr. Water was added and it wasextracted with chloroform and dried over sodium sulfate and evaporatedto give the bromo-alcohol as yellow solid, which was dissolved inmethanol (50 mL) and treated with anhydrous potassium carbonate (5.07g). The mixture was stirred for 3 hr at room temperature then dilutedwith water and extracted with chloroform, dried and evaporated andchromatographed on silica gel (hexane-DCM then chloroform) to afford asolid, which was recrystallised from ether-hexane to give a solid (3.6g).

MS (ES) m/z 237/239 (M+H)⁺.

(f){1-[(Racemic)-2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

A mixture of epoxide (1e) (0.99 g) and piperidin-4-yl-carbamic acidtert-butyl ester (0.84 g) was heated at 100-105° C. for 3 hr, and onedrop of DMF was added and heating was continued for a further 1 hr. Theproduct was dissolved in chloroform and chromatographed on silica gel(methanol-DCM) to afford the solid product (0.78 g) containing ca. 20%of the epoxide ‘wrong-opening’ isomer.

(g)1-[(R/S)-2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-piperidin-4-ylamine

The ester (1f) (0.69 g) in DCM (20 mL) was treated with TFA (20 mL) atroom temperature for 3 hr and evaporated. Water and sodium carbonatewere added and the solution was extracted with 10% methanol-chloroform,dried (sodium sulfate) and evaporated to afford the product as a foamcontaining ca. 20% of the ‘epoxide wrong-opening’ isomer.

(h) 2-Bromo-5-hydroxy-6-nitropyridine

3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol(400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13mole) was added at room temperature. The mixture was stirred for 30 min,then was cooled to 0° C., and bromine (7.2 mL, 0.14 mole) was addedslowly. The reaction was stirred at 0° C. for 30 min, then was quenchedwith glacial AcOH (2.5 mL). The solvent was removed in vacuo to affordmaterial (30 g, 96%), which was used without further purification.

MS (ES) m/z 219.0 (M+H)⁺.

(i) Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate

The hydroxypyridine (1h) (30 g, 0.14 mole) was suspended in acetone (200ml), and potassium carbonate (39 g, 0.28 mole) was added, followed byethyl bromoacetate (15.7 ml, 0.14 mmole). The reaction was heated atreflux for 10 hr, then was cooled to room temperature and diluted withEt₂O. The precipitate was removed by suction filtration, and thefiltrate was concentrated in vacuo to afford material (38 g, 89%), whichwas used without further purification.

MS (ES) m/z 305.0 (M+H)⁺.

(j) 6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one

The nitropyridine (1i) (38 g, 0.125 mole) was dissolved in glacial AcOH(150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture wasmechanically stirred and heated at 90° C. for 5 hr, then was cooled toroom temperature and diluted with EtOAc (300 mL). The mixture wasfiltered through a pad of silica gel and the filtrate was concentratedin vacuo and the residue recrystallized from MeOH (15 g, 52%).

MS (ES) m/z 229.0 (M+H)⁺.

(k) 6-((E)-Styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one

The bromopyridine (1j) (6.0 g, 26.3 mmole) andtrans-2-phenylvinylboronic acid (3.9 g, 26.3 mmole) were dissolved in1,4-dioxane (150 mL) and the solution was degassed with argon. (Ph₃P)₄Pd(230 mg, 0.2 mmole) was added, followed by a solution of potassiumcarbonate (6.9 g, 50 mmole) in H₂O (20 mL). The reaction was heated atreflux under argon overnight, then was cooled to room temperature anddiluted with EtOAc (200 mL). The solution was washed sequentially withH₂O and brine, dried (Na₂SO₄), and concentrated in vacuo. The solidresidue was purified by flash chromatography on silica gel (5-10%EtOAc/CHCl₃) to afford a solid (2.5 g, 38%).

MS (ES) m/z 253.0 (M+H)⁺.

(l) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde

The pyridine (1k) (1.2 g, 4.8 mmole) was dissolved in CH₂Cl₂ (200 mL)and the solution was cooled to −78° C. Ozone was bubbled through thesolution with stirring until a pale blue color appeared, then the excessozone was removed by bubbling oxygen through the solution for 15 min.Dimethylsulfide (1.76 mL, 24 mmole) was added to the solution, and thereaction was stirred at −78° C. for 3 hr, then at room temperatureovernight. The solvent was removed in vacuo, and the residue wastriturated with Et₂O (50 mL). The collected solid was washed withadditional Et₂O and dried to afford a solid (700 mg, 82%).

MS (ES) m/z 179.0 (M+H)⁺.

(m) Title Compound

The amine (1g) (0.4 g) and aldehyde (II) (0.212 g) were dissolved in DMF(7 mL), methanol (7 mL) and acetic acid (0.7 mL) and heated with 3 Amolecular sieves for 2 hr at 75-80° C. for 2 hr, cooled, and treatedwith sodium cyanoborohydride (0.30 g) and the mixture was stirredovernight at room temperature. Chloroform was added and the mixture wasfiltered, treated with sodium carbonate solution and extracted withmethanol-chloroform, dried (sodium sulfate), evaporated andchromatographed on silica gel (methanol-DCM) to afford a solid (0.45 g)which was recrystallised from methanol-ether to afford the pure racemictitle compound (0.30 g) as the free base.

MS (ES) m/z 499/501 (M+H)⁺.

¹H NMR δH (CDCl₃, 400 MHz), 1.40-1.70 (2H, m), 1.88 (2H, br. d), 2.25(2H, q), 2.52 (1H, m), 2.65 (1H, dd), 3.00 (2H, br t), 3.07 (1H, dd),3.80 (2H, s), 4.03 (3H, s), 4.65 (2H, s), 5.67 (1H, m), 6.42 (1H, brd),6.95 (1H, d), 7.15 (2H, 2×d), 8.21 (1H, d), 8.70 (1H, s).

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound.

Example 2(Racemic)-1-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-{4-[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-piperidin-1-yl}-ethanolDihydrochloride (a) 5-Benzyloxy-2-hydroxymethyl-1H-pyridin-4-one

A mixture of 5-benzyloxy-2-hydroxymethyl-4-pyrone (prepared from Kojicacid by the method of D. Erol, J. Med. Chem., 1994, 29, 893) (9.7 g, 40mmol), concentrated aqueous (880) ammonia (100 mL), and ethanol (20 mL)was heated to reflux overnight. The mixture was allowed to cool to roomtemperature then filtered. The resultant solid was washed with ether anddried in vacuo (5.9 g).

MS (APCl+) m/z 232 (MH+).

(b) (2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol

A solution of (2a) (2 g, 8.7 mmol) in water (220 mL) containing sodiumhydroxide (17 mmol) was hydrogenated over 10% palladium on charcoal (1g) for 4 hours. The mixture was filtered and evaporated to give a whitesolid. This solid was dissolved in N,N-dimethylformamide (8 mL) thentreated with potassium carbonate (2.9 g) and 1,2-dibromoethane (0.6 mL,7 mmol). The mixture was heated at 85° C. overnight. The cooled mixturewas evaporated onto silica and chromatographed eluting with 10-30%methanol in ethyl acetate affording a white solid (250 mg, 21%).

MS (APCl+) m/z 168 (MH+).

(c) 2,3-Dihydro-[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde

A solution of (2b) (250 mg, 1.5 mmol) in dichloromethane (5 mL) wastreated with manganese dioxide (650 mg, 7.5 mmol). After 3 days themixture was filtered and evaporated affording a white solid (150 mg,61%).

MS (APCl+) m/z 166 (MH+).

(d) Title Compound

The amine (1g) (0.57 g) and aldehyde (2c) (0.285 g) were dissolved inDMF (10 mL) and sodium triacetoxyborohydride (1.078 g) added and thesolution was stirred overnight at room temperature. Chloroform was addedand the mixture was filtered, treated with sodium carbonate solution andextracted with methanol-chloroform, dried (sodium sulfate), evaporatedand chromatographed on silica gel (methanol-DCM) to afford the free baseof the title compound as a solid (0.52 g), containing ca. 20% of theunwanted ‘epoxide wrong-opening’ isomer.

LC/MS (ES) two peaks Rt 1.31 and 1.21 minutes m/z 486/488 (M+H)⁺.

¹H NMR δH (CDCl₃, 400 MHz), 1.40-1.70 (2H, m), 1.88 (2H, br. d), 2.25(2H, q), 2.52 (1H, m), 2.65 (1H, dd), 3.00 (2H, m), 3.10 (1H, dd), 3.80(2H, s), 4.05 (3H, s), 4.25-4.35 (4H, m), 5.67 (1H, m), 6.38 (1H, br s),6.83 (1H, s), 7.15 (1H, d), 8.05 (1H, s), 8.23 (1H, d), 8.70 (1H, s)(plus impurity peaks).

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wasrecrystallised from methanol to give the pure racemic title compound(0.395 g).

LC/MS (ES) single peak with Rt 1.31 minutes with m/z 486/88 (M+H)⁺.

Example 3{1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amineDihydrochloride (a) 7-Chloro-2-methoxy-8-vinyl-[1,5]naphthyridine

The triflate (1b) (1 g) in DME (20 mL) under argon, was treated withtetrakis(triphenylphosphine)palladium(0) (0.21 g) and the mixturestirred at room temperature for 20 minutes. Anhydrous potassiumcarbonate (0.403 g), water (6 mL), and vinylborane:pyridine complex (seeF. Kerins and D O'Shea J. Org. Chem. 2002, 67, 4968-4971) (1.056 g) wereadded and the mixture was heated at 100° C. for 1.5 hr. It was cooled,diluted with water and extracted with ether, dried (sodium sulfate),evaporated and chromatographed on silica gel, eluting with DCM thenchloroform to afford a white solid (0.53 g).

MS (ES) m/z 221/223 (M+H)⁺.

(b){1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert butyl ester

A mixture of the vinyl-naphthyridine (3a) (0.53 g) andpiperidin-4-yl-carbamic acid tert-butyl ester (0.482 g) was heated at95-100° C. for 10 hr, then the product was dissolved in chloroform andchromatographed on silica gel (DCM then methanol-DCM) to afford thesolid product (0.31 g)

MS (ES) m/z 421/423 (M+H)⁺.

(c)1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-ylamine

The ester (3b) was dissolved in DCM (20 mL) and trifluoroacetic acid (20mL) was added and the solution was left at room temperature for 1 hrthen evaporated to dryness. It was treated with water and sodiumcarbonate and extracted with 1% methanol-chloroform, dried (sodiumsulfate) and evaporated to give a foam (0.24 g).

MS (ES) m/z 321/323 (M+H)⁺.

(d) Title Compound

The amine (3c) (0.24 g) and aldehyde (2c) (0.124 g) were dissolved inDMF (10 mL) and sodium triacetoxyborohydride (0.48 g) added and thesolution was stirred overnight at room temperature. Chloroform was addedand the mixture was filtered, treated with sodium carbonate solution andextracted with methanol-chloroform, dried (sodium sulfate), evaporatedand chromatographed on silica gel (methanol-DCM) to afford the free baseof the title compound as a solid (0.22 g).

MS (ES) m/z 470/472 (M+H)⁺.

¹H NMR δH (CDCl₃, 400 MHz), 1.40-1.60 (2H, m), 1.95 (2H, br. d), 2.25(2H, t), 2.54 (1H, m), 2.70 (2H, m), 3.07 (2H, m), 3.55 (2H, m), 3.78(2H, s), 4.05 (3H, s), 4.25-4.35 (4H, m), 6.82 (1H, s), 7.09 (1H, d),8.10 (1H, s), 8.15 (1H, d), 8.65 (1H, s)

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wastrituated with ether to give the title compound (0.224 g).

Example 4{1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amineDihydrochloride (a) 3-Chloro-6-methoxy-quinolin-4-ol

6-Methoxy-quinolin-4-ol (18.5 g) in acetic acid (750 mL) was treatedwith N-chlorosuccinimide (15.52 g) and the mixture was heated at 60° C.for 4.5 hr, cooled, and evaporated. Excess sodium bicarbonate solutionwas added and the solid collected and washed with water and dried invacuo at 40° C. overnight, to give a yellow solid (21.3 g).

MS (ES) m/z 210/212 (M+H)⁺.

(b) 4-Bromo-3-chloro-6-methoxy-quinoline

The quinolin-4-ol (4a) in dry DMF (80 mL) was cooled in ice andphosphorus tribromide (15.6 mL) added drop-wise, and the mixture wasstirred, with ice-cooling for 30 minutes then allowed to warm to roomtemperature and stirred for a further 3.5 hours. It was cooled in iceand sodium carbonate solution was added and the solid was collected,washed well with water, and dried in vacuo, to afford a pale yellowsolid (13.2 g).

MS (ES) m/z 272/274/276 (M+H)⁺.

(c) 7-Chloro-2-methoxy-8-vinyl-quinoline

The bromide (4b) (0.5 g) in DME (14 mL) under argon, was treated withtetrakis(triphenylphosphine)palladium(0) (0.104 g) and the mixturestirred at room temperature for 20 minutes. Anhydrous potassiumcarbonate (0.25 g), water (4 mL), and vinylborane:pyridine complex wasadded and the mixture was heated at 100° C. for 1 hr. It was cooled,diluted with water and extracted with ether, dried (sodium sulfate) andevaporated to dryness. As starting material (4b) was still present thecrude reaction product was reacted again, as above, and heated for afurther 6 hours. After work-up the product was chromatographed on silicagel, eluting with DCM to afford a white solid (0.35 g).

MS (ES) m/z 220/222 (M+H)⁺.

(d){1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl-carbamicacid tert butyl ester

A mixture of the vinyl-quinoline (4c) (1.1 g) andpiperidin-4-yl-carbamic acid tert-butyl ester (1.17 g) in chloroform (2mL) was heated at 150° C. for 3 days, then the product was dissolved inDCM and chromatographed on silica gel (ethyl acetate-DCM) to afford thesolid product (0.59 g)

MS (ES) m/z 420/422 (M+H)⁺.

(e) 1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylaminedihydrochloride

The ester (4d) (0.59 g) was dissolved in chloroform (15 mL) and asolution of 4M HCl in dioxan (3.5 mL) was added and the solution wasstirred at room temperature for 2.5 hr then evaporated to dryness andazeotroped with toluene to give the product.

MS (ES) m/z 320/322 (M+H)⁺.

(f) Title Compound

The amine (4e) (0.45 g) and aldehyde (2c) (0.24 g) were dissolved in DMF(15 mL) and triethylamine (0.78 mL) added followed by sodiumtriacetoxyborohydride (1.2 g) and the solution was stirred for 2 days atroom temperature. The mixture was quenched with 2N HCl, basified withsodium bicarbonate solution, and extracted with methanol-DCM, dried(sodium sulfate), evaporated and chromatographed on silica gel(methanol-DCM) to afford the free base of the title compound as a solid(0.273 g).

MS (ES) m/z 469/471 (M+H)⁺.

¹H NMR δH (CD₃OD, 250 MHz), 1.55-1.80 (2H, m), 2.10 (2H, br. d), 2.25(2H, t), 2.68 (2H, m), 2.91 (1H, m), 3.30 (2H, m), 3.45 (2H, m), 3.98(3H, s), 4.04 (2H, s), 4.25-4.40 (4H, m), 6.95 (1H, s), 7.40 (1H, s)overlapping with 7.42 (1H, dd), 8.10 (1H, s), 8.60 (1H, s).

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wastriturated with ether to give the title compound (0.33 g).

Example 56-({(cis)-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-oneDihydrochloride Enantiomer 1

(a) cis-4-tert-Butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylicacid benzyl ester. Racemiccis-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester was prepared according to the procedure outlined by Kim etal. [Syn. Comm. 2001, 31, 1081-1089] starting from3,6-Dihydro-2H-pyridine-1-carboxylic acid benzyl ester.

MS (ES) m/z 351 (M+H)⁺.

(b) cis-4-tert-Butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylicacid benzyl ester enantiomer 1 andcis-4-tert-Butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester enantiomer 2

71.0 g of the racemate (5a) was dissolved in methanol (710 mL) andresolved through multiple injections (1×8 g substrate injection; 5×10 gsubstrate injection; 1×7 g substrate injection; and 1×6 g substrateinjection) on a Chiralpak AD column (77×250 mm) eluting with 100%methanol at a flow rate of 280 mL/minute with UV detection at 254 nm.31.15 g ofcis-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester fast running enantiomer (>99% ee, retention time 3.8minutes (sharp), designated enantiomer 1) and 26.75 g ofcis-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester slow running enantiomer (>99% ee, retention time 8.0minutes (very broad), designated enantiomer 2) were obtained.

(c) cis-(3-Hydroxy-piperidin-4-yl)-carbamic acid tert-butyl esterenantiomer 1 and cis-(3-Hydroxy-piperidin-4-yl)-carbamic acid tert-butylester enantiomer 2

10.0 g ofcis-4-tert-Butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester fast running (5b, enantiomer 1), was dissolved in methanol(350 mL) and was degassed. Pearlman's catalyst (palladium hydroxide oncarbon, 20 wt % Pd (dry basis), ≦50% water, 500 mg) was added and themixture was purged with hydrogen and stirring continued under a balloonof hydrogen for 12 hours. The mixture was degassed with argon, filteredthrough a pad of Celite, and evaporated to dryness to afford 6.2 g(100%) a white solid.

MS (ES) m/z 217 (M+H)⁺.

Similarly, the corresponding slower running enantiomer (5b, enantiomer2) was converted to cis-(3-hydroxy-piperidin-4-yl)-carbamic acidtert-butyl ester (5c, enantiomer 2)

(d)cis-{1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3-hydroxy-piperidin-4-yl}-carbamicacid tert-butyl ester enantiomer 1

cis-(3-Hydroxy-piperidin-4-yl)-carbamic acid tert-butyl ester enantiomer1 (5c, enantiomer 1) (473 mg, 2.2 mmole) and vinyl quinoline (4c) (480mg, 2.2 mmole) were dissolved in a minimal amount of chloroform (2 mL)and then heated at 90° C. overnight. Purification by silica gelchromatography with 5% methanol/chloroform gave an oil (550 mg, 58%).

MS (ES) m/z 436 (M+H)⁺.

(e)cis-4-Amino-1-[2-(3-chloro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-3-oldihydrochloride dioxane solvate enantiomer 1

To a stirred solution ofcis{1-[2-(3-chloro-6-methoxy-quinolin-4-yl)-ethyl]-3-hydroxy-piperidin-4-yl}-carbamicacid tert-butyl ester enantiomer 1 (5d, enantiomer 1), (550 mg, 1.3mmole) in chloroform (2 mL) was added 4M HCl in dioxane (5 mL). Stirringwas continued for 2 hours then toluene was added and the mixtureconcentrated under reduced pressure then dried under high vacuum toafford an off white solid (645 mg, 100%).

MS (ES) m/z 336 (M+H)⁺.

(f) Title Compound

A solution ofcis-4-Amino-1-[2-(3-chloro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-3-oldihydrochloride dioxane solvate enantiomer 1 (335 mg, 0.68 mmole) indichloromethane (6 mL) and methanol (2 mL) was treated withtriethylamine (0.47 mL, 3.4 mmole) followed by3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (1l)(120 mg, 0.68 mmole). After stirring overnight the mixure was cooled to0° C. and sodium borohydride (26 mg, 0.68 mmole) was added. The reactionwas stirred 2 hours at 0° C., then diluted with chloroform and washedwith saturated aqueous sodium bicarbonate. The aqueous layer wasextracted with chloroform, and the combined organics were dried oversodium sulfate, filtered and evaporated. The title compound was purifiedby silica gel chromatography eluting with 90:10:1CHCl₃:MeOH:NH₄OH_((aq)) to afford the free base of the title compound(259 mg, 83%).

¹H NMR δH (400 MHz, CDCl₃)

8.64 (s, 1H), 7.99 (d, J=9.2 Hz, 1H), 7.35 (dd, J=2.7, 9.2 Hz, 1H), 7.23(d, J=2.7 Hz, 1H), 7.20 (d, J=8.1Hz, 1H), 4.61 (s, 2H), 3.95 (s, 3H),3.87 (m, 2H), 3.45 (bs, 1H), 3.35 (m, 2H), 3.19 (d, J=10.3, 1H), 3.02(d, J=10.5, 1H), 2.60-2.80 (m, 4H), 2.35 (d, J=11.4, 1H), 2.21 (m, 1H),1.70-1.93 (m, 3H). MS (ES) m/z 571.9 (M+H)⁺.

This material was converted to the dihydrochloride by dissolving inchloroform and adding 2 equivalents of 1M HCl/ether then evaporating todryness.

Example 66-({(cis)-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-oneDihydrochloride Enantiomer 2

The free base was prepared as in Example (5) from (5b)cis-(3-hydroxy-piperidin-4-yl)-carbamic acid tert-butyl ester (5c,enantiomer 2)

¹H NMR δH (400 MHz, CDCl₃)

8.64 (s, 1H), 7.99 (d, J=9.2 Hz, 1H), 7.35 (dd, J=2.7, 9.2 Hz, 1H), 7.23(d, J=2.7 Hz, 1H), 7.20 (d, J=8.1Hz, 1H), 4.61 (s, 2H), 3.95 (s, 3H),3.87 (m, 2H), 3.45 (bs, 1H), 3.35 (m, 2H), 3.19 (d, J=10.3, 1H), 3.02(d, J=10.5, 1H), 2.60-2.80 (m, 4H), 2.35 (d, J=11.4, 1H), 2.21 (m, 1H),1.70-1.93 (m, 3H). MS (ES) m/z 571.9 (M+H)⁺.

This material was converted to the dihydrochloride by dissolving inchloroform and adding 2 equivalents of 1M HCl/ether then evaporating todryness.

Example 76-({(cis)-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride Enantiomer 1 (a) Methyl3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate

A solution of ethyl 2-mercaptoacetate (1.473 mL) in DMF (48 mL) wasice-cooled and treated with sodium hydride (540 mg of a 60% dispersionin oil). After 1 hour methyl 6-amino-5-bromopyridine-2-carboxylate (3g)(T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) was addedand the mixture stirred for 16 hours at room temperature. The solutionwas diluted with EtOAc (1 litre), washed with water (3×300 mL), driedand evaporated to about 10 mL. The white solid was filtered off andwashed with a little EtOAc to give the ester (0.95 g).

MS (APCl⁻) m/z 223 ([M−H]⁻, 100%)

(b) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid

A solution of ester (7a) (788 mg) in dioxan (120 ml)/water (30 mL) wastreated dropwise over 2 hours with 0.5M NaOH solution (8 mL) and stirredovernight. After evaporation to approx. 3 ml, water (5 mL) was added and2M HCl to pH4. The precipitated solid was filtered off, washed with asmall volume of water and dried under vacuum to give a solid (636 mg).

MS (APCl⁻) m/z 209 ([M−H]⁻, 5%), 165([M-COOH]⁻, 100%)

(c) 6-Hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine

A solution of the carboxylic acid (7b) (500 mg) in THF (24 mL) withtriethylamine (0.396 mL) was cooled to −10° C. and isobutylchloroformate (0.339 ml) added. After 20 minutes the suspension wasfiltered through kieselguhr into an ice-cooled solution of sodiumborohydride (272 mg) in water (8 mL), the mixture stirred 30 minutes andthe pH reduced to 7 with dilute HCl. The solvent was evaporated and theresidue triturated under water. The product was filtered and dried undervacuum to give a white solid (346 mg). MS (APCl⁻) m/z 195 ([M−H]⁻, 50%),165(100%)

(d) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde

A solution of the alcohol (7c) (330 mg) in dichloromethane (30 mL)/THF(30 mL) was treated with manganese dioxide (730 mg) and stirred at roomtemperature.

Further manganese dioxide was added after 1 hour (730 mg) and 16 hours(300 mg). After a total of 20 hours the mixture was filtered throughkieselguhr and the filtrate evaporated. The product was triturated withEtOAc/hexane (1:1) and collected to give a solid (180 mg). MS (APCl⁻)m/z 195 ([M−H]⁻, 95%), 165 (100%)

(e) Title Compound

The free base of the title compound was prepared from (5e) as in Example(5f), using the carboxaldehyde (7d).

¹H NMR δH (400 MHz, CDCl₃) δ 8.64 (s, 1H), 7.99 (d, J=9.2 Hz, 1H), 7.57(d, J=7.8 Hz, 1H), 7.35 (dd, J=2.7, 9.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H),6.99(d, J=7.8 Hz, 1H), 3.95 (s, 3H), 3.88 (m, 2H), 3.46 (s, 2H), 3.35(m, 3H), 3.19 (d, J=10.3, 1H), 3.02 (d, J=10.5, 1H), 2.60-2.80 (m, 3H),2.34 (d, J=11.2, 1H), 2.20 (m, 1H), 1.70-1.93 (m, 4H). MS (ES) m/z 587.9(M+H)⁺.

This material was converted to the dihydrochloride by dissolving inchloroform and adding 2 equivalents of 1M HCl/ether then evaporating todryness.

Example 86-({(cis)-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride Enantiomer 2

The free base of the title compound was prepared by the method ofExample (7), using instead cis-(3-hydroxy-piperidin-4-yl)-carbamic acidtert-butyl ester (5c, enantiomer 2)

¹H NMR δH (400 MHz, CDCl₃)

8.64 (s, 1H), 7.99 (d, J=9.2 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.35 (dd,J=2.7, 9.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 6.99(d, J=7.8 Hz, 1H), 3.95(s, 3H), 3.88 (m, 2H), 3.46 (s, 2H), 3.35 (m, 3H), 3.19 (d, J=10.3, 1H),3.02 (d, J=10.5, 1H), 2.60-2.80 (m, 3H), 2.34 (d, J=11.2, 1H), 2.20 (m,1H), 1.70-1.93 (m, 4H). MS (ES) m/z 587.9(M+H)⁺.

This material was converted to the dihydrochloride by dissolving inchloroform and adding 2 equivalents of 1M HCl/ether then evaporating todryness.

Example 96-({(cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-oneDihydrochloride Enantiomer 1

The free base of the title compound was prepared from7-chloro-2-methoxy-8-vinyl-[1,5]naphthyridine (3a) in place of7-chloro-2-methoxy-8-vinyl-quinoline by the method described in Example(5).

¹H NMR δH (CDCl₃, 400 MHz), 8.66 (s, 1H), 8.16 (d, J=9 Hz, 1H), 7.20 (d,J=8 Hz, 1H), 7.10 (d, J=9 Hz, 1H), 6.95 (d, J=8 Hz, 3H), 4.63 (s, 2H),4.08 (s, 3H), 3.91-3.78 (m, 3H), 3.52 (t, J=8 Hz, 2H), 3.15 (m, 2H),2.99 (m, 1H), 2.76 (dd, 13 Hz, 7 Hz), 2.53 (m, 2H), 2.38 (d, J=12 Hz,1H), 2.25 (m, 1H), 1.70 (m, 1H), 1.03 (t, J=7 Hz, 1H). MS (ES) m/z 499(M+H)⁺.

This material was converted to the dihydrochloride by dissolving inchloroform and adding 2 equivalents of 1M HCl/ether then evaporating todryness.

Example 106-({(cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-oneDihydrochloride Enantiomer 2

The free base of the title compound was prepared as described forExample (9) using cis-(3-hydroxy-piperidin-4-yl)-carbamic acidtert-butyl ester (5c, enantiomer 2)

¹H NMR δH (CDCl₃, 400 MHz), 8.66 (s, 1H), 8.16 (d, J=9 Hz, 1H), 7.20 (d,J=8 Hz, 1H), 7.10 (d, J=9 Hz, 1H), 6.95 (d, J=8 Hz, 3H), 4.63 (s, 2H),4.08 (s, 3H), 3.91-3.78 (m, 3H), 3.52 (t, J=8 Hz, 2H), 3.15 (m, 2H),2.99 (m, 1H), 2.76 (dd, 13 Hz, 7 Hz), 2.53 (m, 2H), 2.38 (d, J=12 Hz,1H), 2.25 (m, 1H), 1.70 (m, 1H), 1.03 (t, J=7 Hz, 1H). MS (ES) m/z 499(M+H)⁺.

This material was converted to the dihydrochloride by dissolving inchloroform and adding 2 equivalents of 1M HCl/ether then evaporating todryness.

Example 116-({(cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride Enantiomer 1

The free base of the title compound was prepared as described in Example(7) starting with 7-chloro-2-methoxy-8-vinyl-[1,5]naphthyridine (3a) inplace of 7-chloro-2-methoxy-8-vinyl-quinoline.

¹H NMR δH (CDCl₃, 400 MHz), 8.66 (s, 1H), 8.50 (bs, 1H), 8.16 (d, J=9Hz, 1H), 7.57 (d, J=8 Hz, 1H), 7.10 (d, J=9 Hz, 1H), 7.00 (d, J=8 Hz,1H), 4.08 (s, 3H), 3.91-3.81 (m, 3H), 3.52 (t, J=8 Hz, 2H), 3.46 (s,2H), 3.15 (m, 1H), 2.99 (m, 1H), 2.75 (m, 2H), 2.55 (d, J=9 Hz, 1H),2.37 (d, J=12 Hz, 1H), 2.25 (m, 1H), 1.70 (m, 3H).

MS (ES) m/z 515 (M+H)⁺.

This material was converted to the dihydrochloride by dissolving inchloroform and adding 2 equivalents of 1M HCl/ether then evaporating todryness.

Example 126-({(cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride Enantiomer 2

The free base of the title compound was prepared as described forExample (11) using cis-(3-hydroxy-piperidin-4-yl)-carbamic acidtert-butyl ester (5c, enantiomer 2)

¹H NMR δH (CDCl₃, 400 MHz), 8.66 (s, 1H), 8.50 (bs, 1H), 8.16 (d, J=9Hz, 1H), 7.57 (d, J=8 Hz, 1H), 7.10 (d, J=9 Hz, 1H), 7.00 (d, J=8 Hz,1H), 4.08 (s, 3H), 3.91-3.81 (m, 3H), 3.52 (t, J=8 Hz, 2H), 3.46 (s,2H), 3.15 (m, 1H), 2.99 (m, 1H), 2.75 (m, 2H), 2.55 (d, J=9 Hz, 1H),2.37 (d, J=12 Hz, 1H), 2.25 (m, 1H), 1.70 (m, 3H). MS (ES) m/z 515(M+H)⁺.

This material was converted to the dihydrochloride by dissolving inchloroform and adding 2 equivalents of 1M HCl/ether then evaporating todryness.

Example 136-({1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one Trihydrochloride (a){1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-yl}carbamicacid tert-butyl ester

To a solution of 4-N-Boc-aminopiperidine (0.60 g, 3.01 mmole) in DMF (5mL) at RT was added 3-chloro-6-methoxy-4-vinyl quinoline (0.60 g, 2.74mmole). After 18 h at 100° C., the reaction solution was concentratedunder vacuum and purified by flash chromatography on silica gel(CHCl₃MeOH containing 5% NH₄OH, 9:1) to afford a tan solid (0.97 g,85%).

LC-MS (ES) m/z 420 (M+H)⁺

(b) {1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-ylamine

To a solution of{1-[2-(3-chloro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-yl)carbamicacid tert-butyl ester (13a) (0.97 g, 2.33 mmole) in CH₂Cl₂ at RT wasadded TFA (1:1, v/v). After 2 hrs, the solution was concentrated todryness under vacuum and the residue redissolved in CH₂Cl₂/MeOH (9:1,v/v). The solution was washed with saturated aqueous NaHCO₃ solution,dried over Na₂SO₄, and concentrated under vacuum to give a waxy yellowsolid (0.68 g, 92%).

LC-MS (ES) m/z 320 (M+H)⁺.

(c) Title Compound

To a solution of{1-[2-(3-chloro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-ylamine (13b)(0.16 g, 0.50 mmole) in CH₂Cl₂ (25 mL) and EtOH (25 mL) was added Na₂SO₄(50 mg) and 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde(7d) (0.11 g, 0.55 mmole). After 12 hr at RT, NaBH₄ (21 mg, 0.55 mmole)was added and the reaction solution was allowed to stir overnight.Silica gel (−5 g) was added to the reaction solution and the contentswere concentrated under vacuum. The silica-adsorbed reaction contentswere added directly to a silica gel column and eluted (CHCl₃/MeOHcontaining 5% NH₄OH, 9:1) to give the free base of the title compound(0.21 g, 86%) as an off-white solid:

¹H NMR (400 MHz, d₄-MeOH) 8.76 (s, 1H), 8.00 (d, J=9.2 Hz, 1H), 7.84 (d,J=7.5 Hz, 1H), 7.60 (s, 1H), 7.52 (d, J=9.3 Hz, 1H), 7.18 (d, J=7.5 Hz,1H), 4.47 (s, 2H), 4.12 (s, 3H), 4.01 (m, 2H), 3.91 (m, 2H), 3.57 (s,2H), 3.37 (m, 5H), 2.59 (m, 2H), 2.33 (m, 2H). LC-MS (ES) m/z 498(M+H)⁺.

This material was converted to the hydrochloride salt by dissolving inchloroform and adding 3 equivalents of 1M HCl/ether then evaporating todryness.

Example 146-({1-[2-(3-chloro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one Trihydrochloride

This was prepared by the procedure of Example (13c), except substituting3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (1l)(0.10 g, 0.55 mmole) for3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde, givingthe free base of the title compound (0.19 g, 81%) as an off-white solidfollowing flash chromatography on silica gel (CHCl₃/MeOH, 9:1,containing 5% NH₄OH).

¹H NMR (400 MHz, d₄-MeOH) 8.85 (s, 1H), 8.03 (d, J=9.2 Hz, 1H), 7.93 (s,1H), 7.60 (d, J=7.5 Hz, 1H), 7.57 (m, 1H), 7.17 (m, 1H), 4.40 (s, 2H),4.13 (s, 3H), 4.09 (m, 2H), 3.95 (m, 2H), 3.71 (m, 2H), 3.53 (s, 2H),3.37 (m, 3H), 2.59 (m, 2H), 2.32 (m, 2H). LC-MS (ES) m/z 482 (M+H)⁺.

This material was converted to the hydrochloride salt by dissolving inchloroform and adding 3 equivalents of 1M HCl/ether then evaporating todryness.

Example 156-({1-[2-(3-Chloro-6-methoxynaphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one Dihydrochloride

This was prepared by the procedure of Example (13c), except substituting1-[2-(3-chloro-6-methoxynaphthyridin-4-yl)ethyl]piperidin-4-ylamine(0.18 g, 0.56 mmole) [prepared from 4-N-Boc-aminopiperidine and7-chloro-2-methoxy-8-vinyl-[1,5]naphthyridine (3a)] by the method ofExamples (13a/b) to give the free base of the title compound (0.15 g,53%), as an off-white solid following flash chromatography on silica gel(CHCl₃/MeOH, 9:1, containing 5% NH₄OH).

¹H NMR (400 MHz, d₆-DMSO) 8.84 (s, 1H), 8.33 (d, J=9.0 Hz, 1H), 7.91 (d,J=7.8 Hz, 1H), 7.34 (d, J=9.0 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 4.25 (m,2H), 4.12 (s, 3H), 3.81 (m, 4H), 3.61 (s, 2H), 3.49 (m, 1H), 3.27 (m,2H), 3.11 (m, 2H), 2.51 (m, 2H), 2.20 (m, 2H). LC-MS (ES) m/z 499(M+H)⁺.

This material was converted to the hydrochloride salt by dissolving inchloroform and adding 2 equivalents of 1M HCl/ether then evaporating todryness.

Example 166-({1-[2-(3-chloro-6-methoxynaphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one Dihydrochloride

This was prepared according to the procedure of Example (13c), exceptsubstituting1-[2-(3-chloro-6-methoxynaphthyridin-4-yl)ethyl]piperidin-4-ylamine(0.18 g, 0.56 mmole) for1-[2-(3-chloro-6-methoxyquinolinyl-4-yl)ethyl]piperidin-4-ylamine, andsubstituting3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (1l)(0.10 g, 0.56 mmole) for3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde, togive the free base of the title compound (0.23 g, 84%), as an off-whitesolid following flash chromatography on silica gel (CHCl₃/MeOH, 9:1,containing 5% NH₄OH).

¹H NMR (400 MHz, d₆-DMSO) 8.84 (s, 1H), 8.33 (d, J=9.0 Hz, 1H), 7.47 (d,J=8.0 Hz, 1H), 7.34 (d, J=9.1Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 4.70 (m,2H), 4.18 (m, 2H), 4.12 (s, 3H), 3.81 (m, 4H), 3.42 (m, 1H), 3.38 (m,2H), 3.25 (m, 2H), 2.40 (m, 2H), 2.18 (m, 2H). LC-MS (ES) m/z 483(M+H)⁺.

This material was converted to the hydrochloride salt by dissolving inchloroform and adding 2 equivalents of 1M HCl/ether then evaporating todryness.

Example 176-({(trans)-1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]3-hydroxypiperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one Trihydrochlorideenantiomer 2 (a) N-Carbobenzoxy-1,2,3,6-tetrahydropyridine

20 g (0.24 mole) of 1,2,3,6 tetrahydropyridine was added to 25 mL of 10%aqueous Na₂CO₃ and cooled to 0 C. 34.3 mL (0.24 mole) of benzylchloroformate was added dropwise over 1 hr. The contents were allowed tostir overnight, coming to room temperature during the interim. Thereaction mixture was diluted with 500 mL of brine, and extracted severaltimes with Et₂O. The organic layers were combined, dried over MgSO₄,filtered, and evaporated to dryness. The crude material was purified byflash chromatography on silica gel using 10% EtOAc/Hexanes as the eluentto give (24.5 g, 47%).

¹H NMR (MeOD, 400 MHz)

7.38-7.29 (m, 5H), 6.04-5.93 (m, 1H), 5.83-5.72 (m, 1H). 5.15 (s, 2H),4.09-3.98 (m, 2H), 3.72-3.62 (m, 2H), 2.24-2.18 (m, 2H). LC-MS (ES) m/z218 (M+H)⁺.

(b) N-Carbobenzoxy-3,4-epoxypiperidine

To a cooled (0° C.) solution ofN-carbobenzoxy-1,2,3,6-tetrahydropyridine (17a) (24.5 g, 0.11 mole) in200 mL of DCM, was added a solution of m-chloroperbenzoic acid (27 g,0.16 mole) in 200 mL of DCM dropwise over 30 min. The contents wereallowed to warm to room temperature and continue to stir for 4 hrs. Thereaction mixture was then washed (3×300 mL) with 5% aq. K₂CO₃ and (3×300mL) with brine. The organic fraction was dried with MgSO₄, filtered andevaporated to a colorless oil. The crude material was purified by flashchromatography on silica gel using 20% EtOAc/hexanes as the eluent togive 23.1 g (91%).

¹H NMR (MeOD, 400 MHz) δ 7.38-7.29 (m, 5H), 5.12 (s, 2H), 4.01-3.87 (m,2H) 3.43-3.25 (m, 4H), 2.15-2.90 (m, 2H). LC-MS (ES) m/z 234 (M+H)⁺

(c) N-Carbobenzoxy-trans-3-hydroxy-4-azidopiperidine

10.6 g (0.2 mole) of NH₄Cl was dissolved in 30 mL of water. Thissolution was then diluted to 8:1 with MeOH (240 mL). To the solution wasadded 23.7 g (0.1 mole) of N-carbobenzoxy-3,4-epoxypiperidine (17b),followed by 6.5 g (0.12 mole) of sodium azide. The contents were heatedto 65° C. overnight. The contents were concentrated down by rotaryevaporation (approx. 50 mL), and partioned between EtOAc (300 mL) andwater (300 mL). The organic layer was further washed with water (1×200mL) and brine (2×250 mL). Organic layer was then dried over MgSO₄,filtered and evaporated to dryness. Crude material was purified by flashchromatography on silica gel using 30% EtOAc/hexanes to give 20.5 g(74%).

¹H NMR (DMSO, 400 MHz) δ7.24-7.15 (m, 5H), 5.48-5.47 (m, 1H), 4.90 (s,2H) 3.84-3.70 (m, 2H), 3.32-3.12 (m, 2H), 2.95-2.55 (m, 2H), 1.73-1.69(m, 1H), 1.16-1.06 (m, 1H). LC-MS (ES) m/z 277 (M+H)⁺

(d) N-Carbobenzoxy-trans-3-hydroxy-4-aminopiperidine

20 g of N-Carbobenzoxy-trans-3-hydroxy-4-azidopiperidine (17c) wasdissolved in 300 mL of EtOAc and degassed several times from alternatingvacuum/N₂. 1.0 g of 5% Pd/C (Degussa type) was added and the contentswere degassed again before being placed under atmospheric H₂ overnight.The following day, a tlc sample indicated the reaction was not complete.500 mg of 10% Pd/C was added, the contents degassed and placed underatmospheric H₂ for 4 hrs. Reaction was nearly complete by tlc. Thecontents were filtered through a pad of Celite, and the Celite washedwith MeOH. The solution was evaporated to dryness and purified by flashchromatography on silica gel using 10% MeOH/DCM and going to 90:10:1DCM/MeOH/NH₄OH as the elution system to give 11.4 g (63%).

¹H NMR (CDCl₃, 400 MHz)

7.16-7.07 (m, 5H), 4.89 (s, 2H), 4.19-3.91 (m, 2H), 3.12-3.02 (m, 1H),2.78-2.68 (m, 1H), 2.60-2.47 (m, 2H), 1.83-1.76 (m, 1H), 1.33-1.25 (m,1H).

LC-MS (ES) m/z 251 (M+H)⁺

(e) racemictrans-4-tert-Butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester

11.4 g (45.6 mmol) of N-carbobenzoxy-trans-3-hydroxy-4-aminopiperidine(17d) was dissolved in 200 mL of DCM. A solution of di-tert-butyldicarbonate (9.94 g, 45.6 mmol) in 50 mL of DCM was added slowly viaaddition funnel. The contents were allowed to stir overnight at roomtemperature. The contents were evaporated to dryness, to give (16g)(quant).

¹H NMR (DMSO, 400 MHz)

7.38-7.32 (m, 5H), 6.83 (d, 1H), 5.06 (s, 2H), 5.01 (m, 1H), 3.98-3.79(m, 2H), 3.34-3.26 (m, 2H), 3.95-3.62 (m, 2H), 1.95-1.90 (m, 1H), 1.38(s, 9H), 1.32-1.25 (m, 1H). LC-MS (ES) m/z 351 (M+H)⁺

(f) trans-4-tert-Butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylicacid benzyl ester enantiomer 1 andtrans-4-tert-Butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester enantiomer 2

14.0 g of the racemictrans-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester (17e) was dissolved in methanol (288 mL) and resolvedthrough multiple injections (2×1 g substrate injection; 6×2 g substrateinjection) on a Chiralpak AD column (77×250 mm) eluting with 100%methanol at a flow rate of 280 mL/minute with UV detection at 254 nm.6.23 g oftrans-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester fast running enatiomer (99% ee, retention time 3.8 minutes,designated enantiomer 1) and 6.10 g oftrans-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester slow running enantiomer (99% ee, retention time 6.4minutes, designated enantiomer 2) were obtained.

(g) Title Compound

This was prepared by hydrogenation of piperidine (17f, enantiomer 2)(0.31 g) over Pearlman's catalyst by the method of Example (5c),followed by reaction with the vinyl quinoline (4c), removal of the Bocprotecting group, and reaction with the carboxaldehyde (7d) by themethods of Example (5d-f) to give the free base of the title compound(0.39 g, 86%) as an off-white solid following flash chromatography onsilica gel (CHCl₃/MeOH, 9:1, containing 5% NH₄OH)

¹H NMR (400 MHz, d₄-MeOH) 8.66 (s, 1H), 7.94 (m, 1H), 7.82 (d, J=7.8 Hz,1H), 7.53 (s, 1H), 7.45 (d, J=9.2 Hz, 1H), 7.19 (d, J=7.8 Hz), 4.53 (s,2H), 4.45 (m, 1H), 4.09 (s, 3H), 3.85 (m, 4H), 3.59 (m, 1H), 3.53 (s,2H), 3.42 (m, 3H), 3.21 (m, 1H), 2.67 (m, 1H), 2.32 (m, 1H). LC-MS (ES)m/z 514 (M)⁺.

This material was converted to the hydrochloride salt by dissolving inchloroform and adding 3 equivalents of 1M HCl/ether then evaporating todryness.

Example 186-({(trans)-1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]3-hydroxypiperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one Trihydrochlorideenantiomer 2

This was prepared fromtrans-4-amino-1-[2-(3-chloro-6-methoxyquinolin-4-yl)ethyl]piperidin-3-olenantiomer 2 [prepared from Example (17f, enantiomer 2) byhydrogenation] (0.31 g) by the method of Example (17g) using3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (1l) togive the free base of the title compound (0.37 g, 81%), as an off-whitesolid following flash chromatography on silica gel (CHCl₃/MeOH, 9:1,containing 5% NH₄OH).

¹H NMR (400 MHz, d₄-MeOH) 8.60 (s, 1H), 7.93 (m, 1H), 7.45 (m, 3H), 7.14(d, J=8.1Hz), 4.70 (s, 2H), 4.43 (s, 1H), 4.20 (m, 1H), 4.05 (s, 3H),3.68 (m, 4H), 3.32 (m, 2H), 3.14 (m, 2H), 2.80 (m, 2H), 2.49 (m, 1H),2.05 (m, 1H). LC-MS (ES) m/z 498 (M+H)⁺.

This material was converted to the hydrochloride salt by dissolving inchloroform and adding 3 equivalents of 1M HCl/ether then evaporating todryness.

Example 196-(trans)-1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]3-hydroxypiperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one Trihydrochlorideenantiomer 1

This was prepared fromtrans-4-amino-1-[2-(3-chloro-6-methoxyquinolin-4-yl)ethyl]piperidin-3-olenantiomer 1 (0.31 g) [prepared from Example (17f, enantiomer 1) byhydrogenation] by the method of Example (17g) to give the free base ofthe title compound (0.39 g, 86%), as an off-white solid following flashchromatography on silica gel (CHCl₃/MeOH, 9:1, containing 5% NH₄OH).

¹H NMR (400 MHz, d₄-MeOH) 8.66 (s, 1H), 7.94 (m, 1H), 7.82 (d, J=7.8 Hz,1H), 7.53 (s, 1H), 7.45 (d, J=9.2 Hz, 1H), 7.19 (d, J=7.8 Hz), 4.53 (s,2H), 4.45 (m, 1H), 4.09 (s, 3H), 3.85 (m, 4H), 3.59 (m, 1H), 3.53 (s,2H), 3.42 (m, 3H), 3.21 (m, 1H), 2.67 (m, 1H), 2.32 (m, 1H). LC-MS (ES)m/z 514 (M)+

This material was converted to the hydrochloride salt by dissolving inchloroform and adding 3 equivalents of 1M HCl/ether then evaporating todryness.

Example 206-(trans)-1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]3-hydroxypiperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one Trihydrochlorideenantiomer 1

This was prepared fromtrans-4-amino-1-[2-(3-chloro-6-methoxyquinolin-4-yl)ethyl]piperidin-3-olenantiomer 1 [prepared from Example (17f, enantiomer 1) byhydrogenation] (0.31 g) by the method of Example (17g) using3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (1l) togive the free base of the title compound (0.37 g, 81%), as an off-whitesolid following flash chromatography on silica gel (CHCl₃/MeOH, 9:1,containing 5% NH₄OH).

¹H NMR (400 MHz, d₄-MeOH) 8.60 (s, 1H), 7.93 (m, 1H), 7.45 (m, 3H), 7.14(d, J=8.1Hz), 4.70 (s, 2H), 4.43 (s, 1H), 4.20 (m, 1H), 4.05 (s, 3H),3.68 (m, 4H), 3.32 (m, 2H), 3.14 (m, 2H), 2.80 (m, 2H), 2.49 (m, 1H),2.05 (m, 1H). LC-MS (ES) m/z 498 (M+H)⁺.

This material was converted to the hydrochloride salt by dissolving inchloroform and adding 3 equivalents of 1M HCl/ether then evaporating todryness.

Example 216-({1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]4-hydroxymethylpiperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride (a) 4-Benzyloxycarbonylaminopiperidine-1,4-dicarboxylicacid mono-tert-butyl ester

To a solution of 4-aminopiperidine-1,4-dicarboxylic acid mono-tert-butylester (10.0 g, 40.9 mmole) in 300 mL H₂O, 50 mL 1 N NaOH and 50 mL DMEwas added Cbz-succinimide (15.3 g, 61.4 mmole). After 12 h, the reactionsolution was readjusted to pH=9 with 1N NaOH. After a total of 36 hrs,the reaction solution was concentrated under vacuum, washed with Et₂O(3×200 mL) and acidified to pH=4 with 1M HCl. The reaction contents wereextracted with EtOAc (4×200 mL) and the organics washed with H₂O, brineand then dried over Na₂SO₄ and concentrated. Et₂O was added to theresidue for trituration and the remaining solid was filtered to give awhite solid (12.0 g, 78%). LC-MS (ES) m/z 379 (M+H)⁺.

(b) 4-Benzyloxycarbonylaminopiperidine-1,4-dicarboxylicacid-1-tert-butyl ester-4-methyl ester

To a solution of 4-benzyloxycarbonylaminopiperidine-1,4-dicarboxylicacid mono-tert-butyl ester (21a) (12.0 g, 31.7 mmole) in acetone at RTwas added K₂CO₃ (8.75 g, 63.4 mmole) and methyl iodide (4.95 g, 34.9mmole). After 36 h, the reaction solution was filtered through asinter-glass funnel and the filtrate partitioned between CH₂Cl₂/H₂O (400mL, 1:1, v/v). The phases were separated and the organic phase waswashed with 1N HCl, brine and then concentrated under vacuum. Theresidual oil was purified on silica (hexanes/EtOAc, 1:1) to give acolorless oil (11.2 g, 90%).

LC-MS (ES) m/z 393 (M+H)⁺.

(c) 4-Benzyloxycarbonylaminopiperidine-4-carboxylic acid methyl ester

To a solution of 4-benzyloxycarbonylaminopiperidine-1,4-dicarboxylicacid-1-tert-butyl ester-4-methyl ester (21b) (11.2 g, 28.5 mmole) inCH₂Cl₂ (250 mL) at RT was added TFA (50 mL). After 3 h, the reactionsolution was concentrated under vacuum and the residue dissolved inCH₂Cl₂ (200 mL) and MeOH (20 mL). The solution was washed with saturatedNaHCO₃ solution, dried over Na₂SO₄ and concentrated to a waxy off-whitesolid which was used directly without further purification.

LC-MS (ES) m/z 293 (M+H)⁺.

(d)4-Benzyloxycarbonylamino-1-[2-(3-chloro-6-methoxyquinolin-4-yl)ethyl]piperidine-4-carboxylicacid methyl ester

To a solution of 4-benzyloxycarbonylaminopiperidine-4-carboxylic acidmethyl ester (21c) (1.33 g, 4.56 mmole) in DMF (5 mL) at RT was added7-chloro-2-methoxy-8-vinyl-quinoline (4c) (1.0 g, 4.56 mmole). After 18h at 100° C., the reaction solution was concentrated under vacuum andpurified by flash chromatography on silica gel (CHCl₃/MeOH containing 5%NH₄OH, 9:1) to afford an off-white solid (1.84 g, 79%).

LC-MS (ES) m/z 512 (M+H)⁺

(e)(4-amino-1-[2-(3-chloro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-yl)methanol

To a solution of4-benzyloxycarbonylamino-1-[2-(3-chloro-6-methoxyquinolin-4-yl)ethyl]piperidine-4-carboxylicacid methyl ester (21d) (0.11 g, 0.21 mmole) in EtOH (40 mL) at RT wasadded Pd(OH)₂. After 12 hrs under a balloon of H₂, the reaction solutionwas filtered through Celite (MeOH) and the filtrate concentrated todryness under vacuum. The colorless residue was dissolved in THF (10mL), cooled to 0° C. and LiAlH₄ (0.21 mmole, 1M in THF) was added. After1.5 h, 1M NaOH solution (10 mL) was added and the solution extractedwith CH₂Cl₂. The organic solution was dried over Na₂SO₄, andconcentrated under vacuum to give a colorless oil, which was useddirectly in the following step.

LC-MS (ES) m/z 350 (M+H)⁺.

(f) Title Compound

To a solution of{4-amino-1-[2-(3-chloro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-yl}methanol(21e) (0.05 g, 0.14 mmole) in CH₂Cl₂ (25 mL) and EtOH (25 mL) was addedNa₂SO₄ (50 mg) and3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (7d) (0.04 g,0.2 mmole). After 12 hr at RT, NaBH₄ (5 mg, 0.14 mmole) was added andthe reaction solution was allowed to stir overnight. Silica gel (−5 g)was added to the reaction solution and the contents were concentratedunder vacuum. The silica-adsorbed reaction contents were added directlyto a silica gel column and eluted (CHCl₃/MeOH containing 5% NH₄OH, 9:1)to give the free base of the title compound (0.06 g, 82%) as anoff-white solid.

¹H NMR (400 MHz, d₄-MeOH) 8.64 (s, 1H), 7.95 (m, 2H), 7.83 (d, J=7.8 Hz,1H), 7.52 (s, 1H), 7.43 (d, J=9.2 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 4.41(s, 2H), 4.09 (s, 3H), 3.90 (m, 2H), 3.83 (m, 2H), 3.58 (s, 2H), 3.33(m, 4H), 2.50 (m, 4H), 2.33 (m, 2H). LC-MS (ES) m/z 528 (M+H)⁺.

This material was converted to the hydrochloride salt by dissolving inchloroform and adding 2 equivalents of 1M HCl/ether then evaporating todryness

Example 226-({1-[2-(3-Chloro-6-fluoro-5-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride (a) Carbonic acid 4-bromo-2-fluoro-phenyl ester ethylester

A solution of 4-bromo-2-fluorophenol (25 g, 130 mmol) and triethylamine(21.6 mL, 155 mmol) in dichloromethane (120 mL) was treated at 0° C.with ethyl chloroformate (14.8 mL, 155 mmol). The reaction mixture wasstirred at ambient temperature for 1.5 hours then washed with water,dried and evaporated affording an oil (32 g, 93%). MS (+ve ionelectrospray) m/z 264 (MH⁺).

(b) 4-Bromo-2-fluoro-5-nitro-phenol

A solution of (22a) (32 g, 122 mmol) in concentrated sulphuric acid (55mL) was added dropwise to fuming nitric acid (8.4 mL, 195 mmol) whilemaintaing the temperature between 10-20° C. by the use of an ice-watercooling bath (CAUTION—careful temperature monitoring required). After 2hours the reaction mixture was poured onto ice-water and extractedseveral times with ethyl acetate. The combined organic extracts weredried and evaporated affording an oil (35g). This was dissolved inmethanol (200 mL) and treated with sodium hydrogen carbonate (19 g, 227mmol). The mixture was stirred at 60° C. for 4 hours then concentratedto near-dryness. Water (60 mL) was added and 5M hydrochloric acid addeduntil pH 5 was attained. The reaction mixture was extracted severaltimes with ethyl acetate. The combined organic extracts were dried andevaporated affording an oil (29 g, 83%).

MS (+ve ion electrospray) m/z 237 (MH⁺).

(c) 1-Bromo-5-fluoro-4-methoxy-2-nitro-benzene

A solution of (22b) (25 g, 106 mmol) in DMF (200 mL) was treated withpotassium carbonate (27 g, 198 mmol) and methyl iodide (12 mL, 198 mmol)then heated at 60° C. for 5 hours. The mixture was evaporated and theresidue was partitioned between ethyl acetate and water. The aqueousextract was further extracted with ethyl acetate and the combinedorganic extracts dried and evaporated affording an oil (25.6 g, 97%). MS(+ve ion electrospray) m/z 251 (MH⁺).

(d) 2-Bromo-4-fluoro-5-methoxy-phenylamine

A mixture of (22c) (25.5 g, 96 mmol), acetic acid (250 mL), ethanol (250mL) and iron powder (21.5 g, 385 mmol) was heated at 100° C. for 4hours. After allowing to cool to room temperature, the mixture wasdiluted with water (500 mL) and neutralised with solid potassiumcarbonate. The mixture was filtered through Kieselguhr and extracted (3times) with dichloromethane. This was concentrated to approximately 300mL and passed through a plug of silica gel. Evaporation afforded anorange solid (15.0, 67%). MS (+ve ion electrospray) m/z 221 (MH⁺).

(e)5-[(2-Bromo-4-fluoro-5-methoxy-phenylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione

A mixture of amine (22d) (15 g, 68 mmol), triethyl orthoformate (13.6mL, 82 mmol) and 2,2-dimethyl-[1,3]dioxane-4,6-dione (Meldrums acid)(11.8 g, 82 mmol) in ethanol (70 mL) was heated to reflux under argonfor 2 hours. The resulting precipitate was isolated by filtration thenwashed with cold ethanol then ether and dried in vacuo to afford ayellow solid (23.3 g, 92%). MS (+ve ion electrospray) m/z 374 (MH⁺).

(f) 8-Bromo-6-fluoro-5-methoxy-1H-quinolin-4-one

Dowtherm® A (30 mL) was heated to reflux under a gentle stream of argonand (22e) (10 g, 26.3 mmol) was added portionwise over 2 minutes(CAUTION—rapid evolution of carbon dioxide and acetone). The mixture washeated for a further 2 minutes then allowed to cool to room temperature.A solid was filtered off, which was dissolved withdichloromethane/methanol and dry-loaded onto silica. The filtrate wasalso added to the column, then elution with dichloromethane afforded ayellow solid (2.5 g, 34%). MS (+ve ion electrospray) m/z 272 (MH⁺).

(g) 6-Fluoro-5-methoxy-1H-quinolin-4-one

A solution of (22f) (3.5 g, 12.8 mmol) in aqueous sodium hydroxidesolution (2M, 13 mL, 26 mmol)/dioxan (300 mL)/water (100 mL) washydrogenated over 10% palladium on charcoal (1.5 g) for 60 hours. Themixture was filtered through Kieselguhr and acidified to pH7 withconcentrated hydrobromic acid. The mixture was evaporated and theresidue partitioned between ethyl acetate and water. The ethyl acetateextract was dried and concentrated whereupon crystallisation commenced.Filtration and drying under vacuum afforded a white crystalline solid(1.5 g, 60%). MS (+ve ion electrospray) m/z 194 (MH⁺).

(h) 3-Chloro-6-fluoro-5-methoxy-1H-quinolin-4-one

6-Fluoro-5-methoxy-1H-quinolin-4-one (22f) (0.4 g) in acetic acid (8 mL)was sonicated and warmed until all had dissolved, and then it wastreated with N-chlorosuccinimide (281 mg) and the mixture was heated at50° C. for 3 hr, cooled, and the solid collected and washed with aceticacid and dried in vacuo to give a white solid (0.33 g). MS (ES) m/z228/230 (M+H)⁺.

(i) 4-Bromo-3-chloro-6-methoxy-quinoline

3-Chloro-6-fluoro-5-methoxy-1H-quinolin-4-one (22h) (0.33 g) in dry DMF(5 mL) was cooled in ice and phosphorus tribromide (0.2 mL) addeddrop-wise, and the mixture was stirred, with ice-cooling for 30 minutesthen allowed to warm to room temperature and stirred for a further 2hours. It was cooled in ice and sodium bicarbonate solution was addedand the mixture was extracted with ethyl acetate, dried (magnesiumsulfate), evaporated and dried in vacuo, to afford a yellow solid (0.16g). MS (ES) m/z 290/292/294 (M+H)⁺.

(j) 3-Chloro-6-fluoro-5-methoxy-4-vinyl-quinoline

The bromide (22i) (0.16 g) in DME (5 mL) under argon, was treated withtetrakis(triphenylphosphine)palladium(0) (0.072 g) and the mixturestirred at room temperature for 20 minutes. Anhydrous potassiumcarbonate (0.083 g), water (1.5 mL), and vinylborane:pyridine complex(150 mg) was added and the mixture was heated at 100° C. for 1 hr. Itwas cooled, diluted with water and extracted with ether, dried(magnesium sulfate) and evaporated to dryness. After work-up the productwas chromatographed on silica gel (hexane-ethyl acetate) to afford awhite solid (0.14 g). MS (ES) m/z 238/240 (M+H)⁺.

(k){1-[2-(3-Chloro-6-fluoro-5-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

A mixture of the vinyl-quinoline (22j) (0.14 g) andpiperidin-4-yl-carbamic acid tert-butyl ester (0.12 g) in chloroform (1mL) was heated at 150° C. for 3 days, then the product was dissolved inDCM and chromatographed on silica gel (ethyl acetate-hexane) to affordthe solid product (0.02 g). MS (ES) m/z 438/440 (M+H)⁺.

(l)1-[2-(3-Chloro-6-fluoro-5-methoxy-quinolin-4-yl}-ethyl]-piperidin-4-ylaminedihydrochloride

The ester (22k) (0.02 g) was dissolved in chloroform (0.5 mL) and asolution of 4M HCl in dioxan (1.0 mL) was added and the solution wasstirred at room temperature for 1 hr then evaporated to dryness andazeotroped with toluene to give the product. MS (ES) m/z 338/340 (M+H)⁺.

(m) Title Compound

The amine (22l) (0.015 g) and aldehyde (7d) (0.012 g) were dissolved indichloromethane (4 ml), methanol (1 ml) and triethylamine (0.042 ml) andstirred for 18 hours. Methanol (1 ml) and sodium borohydride (0.002 g)were added and the solution was stirred for 15 min at room temperature.The mixture was quenched with 2N HCl, basified with sodium bicarbonatesolution, and extracted with methanol-DCM, dried (magnesium sulfate),evaporated and chromatographed on silica gel (methanol-DCM) to affordthe free base of the title compound as a solid (0.011 g).

¹H NMR (400 MHz, d₄-MeOH) 8.71 (s, 1H), 7.78 (m, 1H), 7.71 (d, J=7.8 Hz,1H), 7.65 (m, 1H), 7.04 (d, J=7.8 Hz, 1H), 4.12 (s, 3H), 3.92 (s, 2H),3.71 (m, 2H), 3.52 (m, 2H), 3.31 (m, 2H), 3.15 (m, 2H), 2.71 (m, 2H),2.31 (m, 2H), 2.04 (m, 2H). LC-MS (ES) m/z 516/518 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wastriturated with ether to give the title compound (0.012 g).

Example 236-({1-[2-(3-Chloro-6-methyl-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride (a) 6-Methyl-pyridin-3-ylamine

Bromine (19.0 ml) was added to a solution of NaOH (50 g) in water (990ml) at 0° C. with stirring. 6-Methyl-nicotinamide was then added insmall portions keeping the temperature below 5° C. The mixture washeated at 80° C. for 18 h and then cooled and extracted withdichloromethane (6×200 ml). The combined organics were then dried(MgSO4) and then evaporated to give the desired product (58%). MS (+veion electrospray) m/z 108 (MH⁺).

(b)2,2,-Dimethyl-5-[(6-methyl-pyridin-3-ylamino)-methylene-[1,3]dioxane-4,6-dione

A mixture of amine (23a) (46.5 g), triethyl orthoformate (72 ml) and2,2-dimethyl-[1,3]dioxane-4,6-dione (Meldrums acid) (62 g) in ethanol(300 mL) was heated to reflux under argon for 2 hours. The resultingprecipitate was isolated by filtration then washed with cold ethanolthen ether and dried in vacuo to afford a yellow solid (89 g, 80%). MS(+ve ion electrospray) m/z 261 (MH⁺).

(c) 6-Methyl-1H-[1,5]naphthyridin-4-one

Dowtherm® A (100 mL) was heated to reflux under a gentle stream of argonand (23b) (18 g) was added portionwise over 2 minutes (CAUTION—rapidevolution of carbon dioxide and acetone). The mixture was heated for afurther 2 minutes then allowed to cool to room temperature. A solid wasfiltered off, which was dissolved with dichloromethane/methanol anddry-loaded onto silica. The filtrate was also added to the column, thenelution with dichloromethane afforded a yellow solid (6.4 g, 30%). MS(+ve ion electrospray) m/z 160 (MH⁺).

(d) 3-Chloro-6-methyl-1H-[1,5]naphthyridin-4-one

6-Methyl-1H[1,5]naphthyridin-4-one (23c) (14 g) in acetic acid (250 mL)was sonicated and warmed until all had dissolved, and then it wastreated with N-chlorosuccinimide (12 g) and the mixture was heated at50° C. for 3 hr, cooled, and the solid collected and washed with aceticacid and dried in vacuo to give a white solid (7.2 g, 41%). MS (ES) m/z194/196 (M+H)⁺.

(e) 8-Bromo-7-chloro-2-methyl-[1,5]naphthyridine

The naphthyridin-4-one (23e) (7.2 g) in dry DMF (90 mL) was cooled inice and phosphorus tribromide (4.2 mL) added drop-wise, and the mixturewas stirred, with ice-cooling for 30 minutes then allowed to warm toroom temperature and stirred for a further 2 hours. It was cooled in iceand sodium bicarbonate solution was added and the mixture was extractedwith ethyl acetate, dried (magnesium sulfate), evaporated and dried invacuo, to afford a yellow solid (1.91 g). MS (ES) m/z 258/260/262(M+H)⁺.

(f) 7-Chloro-2-methyl-8-vinyl[1,5]naphthyridine

The bromide (23e) (1.0 g) in DME (30 mL) under argon, was treated withtetrakis(triphenylphosphine)palladium(0) (0.090 g) and the mixturestirred at room temperature for 20 minutes. Anhydrous potassiumcarbonate (0.534 g), water (9 mL), and vinylborane:pyridine complex (375mg) was added and the mixture was heated at 100° C. for 4 h. It wascooled, diluted with water and extracted with ether, dried (magnesiumsulfate) and evaporated to dryness. After work-up the product waschromatographed on silica gel (hexane-ethyl acetate) to afford a whitesolid (0.70 g, 88%). MS (ES) m/z 205/207 (M+H)⁺.

(g){1-[2-(3-Chloro-6-methyl-[1,5]-naphthyridin-4-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

A mixture of the vinyl compound (23f) (0.36 g) andpiperidin-4-yl-carbamic acid tert-butyl ester (0.35 g) in chloroform (1ml) was heated at 100° C. for 48 h, then the product was dissolved inDCM and chromatographed on silica gel (ethyl acetate-hexane) to affordthe solid product (0.41 g, 58%). MS (ES) m/z 405/407 (M+H)⁺.

(h) 1[2-(3-Chloro-6-methyl-[1,5]-naphthyridin-4-yl)ethyl]-piperidin-4-ylamine

The compound (23g) (0.41 g) was dissolved in chloroform (4 ml) and asolution of 4M HCl in dioxan (12 ml) was added and the solution wasstirred at room temperature for 1 hr then evaporated to dryness. Theresultant solid was dissolved in 10% MeOH/DCM (100 ml), basified withsaturated NaHCO₃ (5 ml) and further extracted with 10% MeOH/DCM (2×100ml). The combined organics were dried (MgSO₄) and evaporated to give thedesired compound (0.31 g, 100%). MS (ES) m/z 305/307 (M+H)⁺.

(i) Title Compound

The amine (23h) (0.102 g) and aldehyde (7d) (0.065 g) were dissolved inchloroform (2 ml) and methanol (2 ml) with 3 A molecular sieves andrefluxed for 4 hours. Sodium triacetoxyborohydride (0.140 g) was addedand the solution was stirred for 18 h at room temperature. The mixturewas evaporated and chromatographed on silica gel (methanol-DCM) toafford the free base of the title compound as a solid (0.14 g, 80%).

¹H NMR (400 MHz, d₄-MeOH) 8.77 (s, 1H), 8.22 (d, J=7.8 Hz, 1H), 7.74 (d,J=7.6 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 4.12 (s,2H), 3.67 (m, 2H), 3.53 (s, 2H), 3.31-3.36 (m, 2H), 3.02-3.015 (m, 1H),2.87-2.91 (m, 2H), 2.91 (s, 3H), 2.75-2.84 (m, 2H), 2.19-2.44 (m, 2H),1.64-1.74 (m, 2H). LC-MS (ES) m/z 483/485 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wastriturated with ether to give the title compound (0.146 g).

Example 24{1-[2-(3-Chloro-6-methyl-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amineDihydrochloride

This was prepared from amine (23h) and aldehyde (2c) by the method ofExample (23i) to give the free base of the title compound (45%).

¹H NMR (400 MHz, d₄-MeOH) 8.78 (s, 1H), 8.23 (d, J=7.5 Hz, 1H), 8.06 (s,1H), 7.62 (d, J=7.5 Hz, 1H), 6.98 (s, 1H), 4.30-4.41 (m, 4H), 4.04 (s,2H), 3.62-3.72 (m, 2H), 3.28-3.33 (m, 2H), 2.92-3.04 (m, 1H), 2.84-2.87(m, 2H), 2.76 (s, 3H), 2.32-2.37 (m, 2H), 2.08-2.12 (m, 2H), 1.58-1.68(m, 2H). LC-MS (ES) m/z 454/456 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wastriturated with ether to give the title compound.

Example 256-({1-[2-(3-Chloro-6-fluoro-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride (a)5-[4-Fluoro-phenyl-amino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione

This was prepared (89%) from 4-fluoro-aniline using the method ofExample (23b) MS (+ve ion electrospray) m/z 264 (MH⁺).

(b) 6-Fluoro-1-H-quinolin-4-one

This was prepared (54%) from (24a) by the method of Example (23c)

MS (+ve ion electrospray) m/z 163 (MH⁺).

(c) 3-Chloro-6-fluoro-1-H-quinolin-4-one

This was prepared (95%) from (24b) by the method of Example (23d)

MS (+ve ion electrospray) m/z 197/199 (MH⁺).

(d) 4-Bromo-3-chloro-6-fluoro-quinoline

This was prepared (69%) from (24c) by the method of Example (23e)

MS (+ve ion electrospray) m/z 260/262/264 (MH⁺).

(e) 3-Chloro-6-fluoro-4-vinyl-quinoline

This was prepared (86%) from (24d) by the method of Example (23f)

MS (+ve ion electrospray) m/z 207/209 (MH⁺).

(f){1-[2-(3-Chloro-6-fluoro-quinolin-4-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert butyl ester

This was prepared (29%) from (24e) by the method of Example (23g)

MS (+ve ion electrospray) m/z 407/409 (MH⁺).

(g) 1-[2-(3-Chloro-6-fluoro-quinolin-4-yl)-ethyl]-piperidin-4-ylamine

This was prepared (80%) from (24f) by the method of Example (23h)

LC-MS (ES) m/z 307/309 (M+H)⁺.

(h) Title Compound

This was prepared as the free base (88%) from (24g) and aldehyde (7d) bythe method of Example (23i)

¹H NMR (400 MHz, d₄-MeOH) 8.75 (s, 1H), 8.106-8.12 (m, 1H), 7.83-7.86(m, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.61-7.76 (m, 1H), 7.07 (d, J=7.6 Hz,1H), 4.11 (s, 2H), 3.54 (s, 2H), 3.44-3.53 (m, 2H), 3.23-3.30 (m, 2H),2.27-3.05 (m, 1H), 2.71-2.74 (m, 2H) 2.25-2.31(m, 2H), 2.11-2.15 (m,2H), 1.64-1.71 (d, 2H).

LC-MS (ES) m/z 485/487 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wastriturated with ether to give the title compound.

Example 26{1-[2-(3-Chloro-6-fluoro-quinolin-4-yl)-ethyl]-piperidin-4-yl}(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amineDihydrochloride

This was prepared as the free base (78%) from the amine (25g) andaldehyde (2c) by the method of Example (23i).

¹H NMR (400 MHz, d₄-MeOH) 8.71 (s, 1H), 8.02-8.09 (m, 2H), 7.78-7.82 (m,1H), 7.58-7.59 (m, 1H), 7.00 (s, 1H), 4.30-4.40 (m, 4H), 4.04 (s, 2H),3.40-3.44 (m, 2H), 3.17-3.19 (m, 2H), 2.86-3.01 (m, 1H), 2.64-2.70 (m,2H), 2.25-2.33 (m, 2H), 2.01-2.14 (m, 2H), 1.67-1.74 (m, 2H). LC-MS (ES)m/z 456/458 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wastriturated with ether to give the title compound.

Example 276-({1-[2-(3,6-Dichloro-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride (a)5-[4-Chloro-phenyl-amino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione

This was prepared (95%) from 4-chloro-aniline using the method ofExample (23b).

MS (+ve ion electrospray) m/z 283/285 (MH⁺).

(b) 6-chloro-1-H-quinolin-4-one

This was prepared from (27a) (56%) by the method of Example (23c)

MS (+ve ion electrospray) m/z 179/181 (MH⁺).

(c) 3,6-Dichloro-1-H-quinolin-4-one

This was prepared from (27b) (60%) by the method of Example (23d).

MS (+ve ion electrospray) m/z 214/216/218 (MH⁺).

(d) 4-Bromo-3,6-dichloro-quinoline

This was prepared from (27c) (69%) by the method of Example (23e).

MS (+ve ion electrospray) m/z 294/296/298/300 (MH⁺).

(e) 3,6-Dichloro-4-vinyl-quinoline

This was prepared from (27d) (75%) by the method of Example (23f).

MS (+ve ion electrospray) m/z 223/225/227 (MH⁺).

(f) {1-[2-(3,6-Dichloro-quinolin-4-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert butyl ester

This was prepared from (27e) (20%) by the method of Example (23g).

MS (+ve ion electrospray) m/z 423/425/427 (MH⁺).

(g) 1-[2-(3,6-Dichloro-quinolin-4-yl)-ethyl]-piperidin-4-ylamine

This was prepared from (27f) (100%) by the method of Example (23h).

LC-MS (ES) m/z 323/325/327 (M+H)⁺.

(i) Title Compound

The free base of the title compound was prepared (45%) from (27g) andaldehyde (7d) by the method of Example (23h).

¹H NMR (400 MHz, d₄-MeOH) 8.80 (s, 1H), 8.18-8.20 (m, 1H), 8.02 (d,J=7.6 Hz, 1H), 7.61-7.76 (m, 2H), 7.02 (d, J=7.6 Hz, 1H), 3.88 (s, 2H),3.61 (s, 2H), 3.42-3.50 (m, 2H), 3.20-3.35 (m, 2H), 3.09-3.14 (m, 1H),2.63-2.66 (m, 2H) 2.22-2.27(m, 2H), 2.04-2.17 (m, 2H), 1.56-1.62 (d,2H). LC-MS (ES) m/z 501/503/505 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wastriturated with ether to give the title compound.

Example 28{1-[2-(3,6-Dichloro-quinolin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl-amineDihydrochloride

This was prepared as the free base (28%) from the amine (27g) andaldehyde (2c) by the method of Example (23i).

¹H NMR (400 MHz, d₄-MeOH) 8.75 (s, 1H), 8.18-8.19 (m, 2H), 7.99-8.02 (m,1H), 7.71-7.75 (m, 1H), 6.96 (s, 1H), 4.28-4.76 (m, 4H), 3.79 (s, 2H),3.39-3.45 (m, 2H), 3.29-3.35 (m, 2H), 3.07-3.12 (m, 2H), 2.56-2.63 (m,3H), 2.15-2.19 (m, 2H), 2.00-2.10 (m, 2H), 1.44-1.53 (m, 2H). LC-MS (ES)m/z 472/474/476 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wastriturated with ether to give the title compound.

Example 29(cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-4-[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-piperidin-3-olDihydrochloride Enantiomer 1 (a)cis-4-Amino-1-[2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-3-olEnantiomer 1

This was prepared from 7-chloro-2-methoxy-8-vinyl-[1,5]naphthyridine(3a) and cis-(3-hydroxy-piperidin-4-yl)-carbamic acid tert-butyl esterenantiomer 1 (5c) by the method of Example (5d) followed by removal ofthe protecting group by treatment with trifluoroacetic acid in DCM, bythe method of Example (1g).

(b) Title Compound

This was prepared as the free base (0.346 g) from the amine (29a) (0.377g) and aldehyde (2c) (0.18 g) by the method of Example (3d), except thatthe compound was chromatographed on silica gel eluting with methanol/DCMthen 0.5% ammonia in 10% methanol/DCM.

¹H NMR δH (CDCl₃, 400 MHz), 8.66 (s, 1H), 8.16 (d, 1H), 8.09 (1H, s),7.10 (d, 1H), 6.84 (d, 1H), 4.30 (m, 4H), 4.08 (s, 3H), 3.88 (1H, s),3.84 (s, 2H), 3.52 (t, 2H), 3.15 (m, 1H), 3.00 (m, 1H), 2.78 (dd, 2H),2.60 (m, 1H), 2.20-2.45 (m, 3H), 1.75 (m, 2H).

MS (ES) m/z 486/488 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wastriturated with ether to give the title compound (0.429 g).

Example 30(cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-4[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-piperidin-3-olDihydrochloride Enantiomer 2 (a)cis-4-Amino-1-[2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-3-olEnantiomer 2

This was prepared from 7-chloro-2-methoxy-8-vinyl-[1,5]naphthyridine(3a) and cis-(3-hydroxy-piperidin-4-yl)-carbamic acid tert-butyl esterenantiomer 2 [prepared from 5b Enantiomer 2 by the method of Example(5c)] by the method of Example (5d) followed by removal of theprotecting group by treatment with trifluoroacetic acid in DCM, by themethod of Example (1g).

(b) Title Compound

This was prepared as the free base (0.34 g) from the amine (30a) (0.26g) and aldehyde (2c) (0.125 g) by the method of Example (3d).

¹H NMR δH (CDCl₃, 400 MHz), 8.68 (s, 1H), 8.17 (d, 1H), 8.09 (1H, s),7.10 (d, 1H), 6.84 (d, 1H), 4.30 (m, 4H), 4.09 (s, 3H), 3.88 (1H, s),3.84 (s, 2H), 3.52 (t, 2H), 3.13 (m, 1H), 2.98 (m, 1H), 2.76 (dd, 2H),2.58 (m, 1H), 2.40 (d, 1H), 2.25 (1H, m), 2.25 (m, 1H), 1.74 (m, 2H). MS(ES) m/z 486/488 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wastriturated with ether to give the title compound (0.39 g).

Example 316-({1-[2-(3-Fluoro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one dihydrochloride (a)4-Chloro-6-methoxyquinoline-3-carboxylic acid

Ethyl 4-chloro-6-methoxyquinoline-3-carboxylate [R. Fryer et al J. Med.Chem. 36, 1669-1673 (1993)] (64.9 g) was partially dissolved in THF (1L) and treated dropwise with aqueous 2M sodium hydroxide (195 mL). Afterovernight stirring, the mixture was neutralised with dilute HCl and THFwas removed in vacuo. The residue was dissolved in water and acidifiedwith dil. HCl. The solid product was collected under suction, washedwell with water and dried in vacuo to give a white solid (56.2 g, 99%).MS (ES) m/z 238/240 (M+H)⁺.

(b) (4-Chloro-6-methoxy-quinolin-3-yl)-carbamic acid tert-butyl ester

To a solution of the acid (31a) (10 g, 41.9 mmol), triethylamine (49 mL)and tert-butanol (63 mL) in dry dimethylformamide (140 mL) was addeddiphenylphosphoryl azide (10 ml, 45.7 mmol). The mixture was heated at100° C. for 1 h, then cooled and evaporated. The residue was dissolvedin dichloromethane and washed with water (some insoluble material wasremoved by filtration). The aqueous phase was extracted withdichloromethane and the combined organics were dried and evaporated.Chromatography on silica (1:1 ether/light petroleum ether) gave thecarbamate (10.11 g, 78%). MS (ES) m/z 309/311 (M+H)⁺, 253/255(M+H-C₄H₈)⁺

(c) 3-Amino-4-chloro-6-methoxyquinoline

The carbamate (31b) (10.11 g, 32.8 mmol) was dissolved indichloromethane (100 mL) and treated with trifluoroacetic acid (100 mL).After 1.75 h standing at room temperature, the mixture was evaporatedand the residue was dissolved in water and basified with aq. sodiumcarbonate. The precipitate was filtered off, dried and recrystalisedfrom dichloromethane (in two crops, with a third crop obtained byaddition of light petrol) to give a white solid (5.91 g, 86%).

MS (ES) m/z 209/211 (M+H)⁺

(d) 4-Chloro-3-fluoro-6-methoxyquinoline

The amine (31c) (10.52 g, 50.5 mmol) was dissolved in dry THF and cooledto −8° C. Nitrosonium tetrafluoroborate (6.48 g, 55.5 mol) was added inportions over 30 min. at <−2° C. The mixture was then stirred at −5 to−2° C. for 30 min., then the yellow precipitate was filtered off, washedwith cold THF and dried, to give a diazonium tetrafluoroborate salt(13.94 g, 90%).

A suspension of this salt (13.51 g) in decahydronaphthalene (mixedisomers, 270 mL) was heated to 175-180° C., held at this temperature for10 min., then cooled. The decahydronaphthalene was decanted off, and theresidue was washed twice with light petrol. Addition of the washings tothe decanted liquor gave a precipitate which was collected and dissolvedin dichloromethane. The gummy residue was extracted twice withdichloromethane, the extracts being diluted with ether and filtered,then combined with the material precipitated from the liquor andevaporated. Chromatography on silica (0-2% methanol/dichloromethane)gave a white solid (2.45 g, 28%). MS (ES) m/z 212 (M+H)+

(e) 3-Fluoro-6-methoxy-4-vinylquinoline

The 4-chloro-3-fluoroquinoline (31d) (2.25 g, 10.7 mmol) was dissolvedin 1,2-dimethoxyethane (80 mL), tetrakis(triphenylphosphine)palladium(0)(0.61 g, 0.53 mmol) was added and the mixture was stirred under argonfor 20 min. Water (30 mL), potassium carbonate (1.48 g, 10.7 mmol) and2,4,6-trivinylcyclotriboroxane-pyridine complex (F. Kerins & D. F.O'Shea, J. Org. Chem., 2002, 67, 4968)(1.93 g, 8.0 mmol) were added andthe mixture was heated under reflux for 24 h. After cooling, ether wasadded and the phases were separated. The aqueous phase was extractedwell with ether, and the combined extracts were dried and evaporated.Chromatography on silica (10-20% ether/light petroleum ether) gave awaxy solid (1.73 g, 80%). MS (ES) m/z 204 (M+H)+

(f){1-[2-(3-Fluoro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

The 4-vinylquinoline (31e) (0.80 g, 3.9 mmol) was heated withpiperidin-4-yl-carbamic acid tert-butyl ester (1.58 g, 7.8 mmol)) anddimethylformamide (1 mL) at 100° C. for 24 h. After cooling, water wasadded and the mixture was extracted with ether and ethyl acetate. Theextracts were dried and evaporated.

Chromatography on silica (2% methanol/dichloromethane) gave the product(0.80 g, 51%). MS (ES) m/z 404 (M+H)+

(g) 1-[2-(3-Fluoro-6-methoxy-quinolin-4-yl}-ethyl]-piperidin-4-ylamine

The carbamate (31f) (0.051 g, 0.13 mmol) was dissolved indichloromethane (1 mL) and treated with trifluoroacetic acid (1 mL). Thesolution was allowed to stand at room temperature for 1.75 h, thenevaporated. The residue was triturated twice with ether, then dissolvedin 10% methanol/dichloromethane and stirred with polymer-bound carbonate(MP-carbonate resin, Argonaut Technologies Inc.: 2.8 mmol/g, 0.24 g) for3 h. The resin was filtered off and washed several times alternatelywith 10% methanol/dichloromethane and methanol. Evaporation of solventgave the amine (0.044 g, >100%), probably still containing sometrifluoroacetate salt. MS (ES) m/z 304 (M+H)+

(h) Title Compound

The crude amine (31g) (assumed 0.13 mmol) and aldehyde (7d) (0.027 g,0.14 mmol) were mixed in dry chloroform (5 mL) and methanol (0.5 mL) andheated under reflux for 5 h. The mixture was cooled, treated with sodiumtriacetoxyborohydride (0.13 g) and stirred at room temperatureovernight. The mixture was washed with aq. sodium bicarbonate, theaqueous phase was re-extracted with 10% methanol/dichloromethane and thecombined organics were washed with brine, dried and evaporated.Chromatography on silica (2-10% methanol/dichloromethane) gave thefree-base of the title compound (0.032 g, 51%).

1H NMR (250 MHz, CDCl3) δ8.58 (1H, d), 8.45 (1H, broad), 8.00 (1H, d),7.57 (1H,d), 7.31 (1H, d), 7.22 (1H, d), 6.99 (1H, d), 3.95 (3H,s), 3.85(2H, s), 3.47 (2H, s), 3.24 (2H, m), 3.04 (2H, m), 2.67 (2H, m), 2.55(1H, m), 2.19 (2H, m), 1.95 (2H, m), 1.51 (2H, m). MS (ES) m/z 482(M+H)+

The free base in dichloromethane/methanol was treated with 2 equivalentsof HCl (0.4M in 1,4-dioxan), followed by evaporation of solvent andtrituration with ether to give the dihydrochloride salt.

Example 32{1-[2-(3-Fluoro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-aminedihydrochloride

The crude amine (31g), [prepared from 1.98 mmol carbamate (Example31f)], and aldehyde (2c) (0.32 g, 1.98 mmol) were dissolved indimethylformamide (20 mL). Sodium triacetoxyborohydride (1.22 g, 5.76mmol) was added and the mixture was stirred at room temperatureovernight. After addition of a small volume (<1 ml) of 5M HCl,approximately half the solvent was removed by evaporation and theresidue was treated with sat.aq. sodium carbonate and water (20 mL.each). The final pH was adjusted to 10-11 and the mixture wasrefrigerated before filtering off the solid, which was washed with waterand dried to give the free-base of the title compound (0.55 g, 61%).

¹H NMR (250 MHz, CDCl₃) δ8.58 (1H, d), 8.11 (1H, s), 8.00 (1H, d), 7.31(1H, d), 7.22 (1H, d), 6.83 (1H, s), 4.33 (2H, m), 4.27 (2H, m), 3.95(3H,s), 3.81 (2H, s), 3.24 (2H, m), 3.02 (2H, m), 2.64(2H, m), 2.54 (1H,m), 2.17 (2H, m), 1.95 (2H, m), 1.50 (2H, m). MS (ES) m/z 453 (M+H)⁺

The free base in dichloromethane was treated with 2 equivalents of HCl(4M in 1,4-dioxan), followed by evaporation of solvent and triturationwith ether to give the dihydrochloride salt.

Example 33cis-4-[(2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-1-[2-(3-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-3-olEnantiomer 2 dihydrochloride (a)cis-{1-[2-(3-Fluoro-6-methoxy-quinolin-4-yl)-ethyl]-3-hydroxy-piperidin-4-yl]-carbamicacid tert-butyl ester enantiomer 2

The vinyl quinoline (31e) (0.38 g, 1.85 mmol) andcis-4-tert-butoxycarbonylamino-3-hydroxy-piperidine enantiomer 2,prepared from the benzyl carbamate (5b, enantiomer2) (0.40 g, 1.85 mmol)by the method of Example 5(c), were heated with dimethylformamide (0.5mL) at 100° C. for 48 h, with addition of 1,1,5,5-tetramethylguanidine(5 drops) after 24 h. Work up as for Example (31f) followed bychromatography on silica (0-4% methanol/dichloromethane) gave a yellowgum (0.33 g, 43%), plus some recovered vinyl compound (60 mg). MS (ES)m/z 420 (M+H)⁺

(b)cis-4-Amino-1-[2-(3-chloro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-3-olenantiomer 2

The tert-butyl carbamate (33a) was deprotected by the method of Example(31g) to give the crude amine. MS (ES) m/z 320 (M+H)⁺

(c) Title Compound

The crude amine (33b) (prepared from 1.79 mmol carbamate) and aldehyde(2c) (0.28 g, 1.70 mmol) were mixed in dry chloroform (5 mL) andmethanol (0.5 mL) and heated under reflux for 5.5 h, with 4 A molecularsieves added after 4 h. The mixture was cooled, treated with sodiumtriacetoxyborohydride (0.38 g) and stirred at room temperature over 2days. A further portion of the borohydride (0.2 g) was added andstirring continued for 8 h. A few drops of 5M HCl were added, then themixture was washed with aq. sodium bicarbonate, the aqueous phase wasre-extracted with 10% methanol/dichloromethane and the combined organicswere washed with brine, dried and evaporated. Chromatography on silica(5-10% methanol/dichloromethane) gave the free-base of the titlecompound (0.44 g, 52%).

¹H NMR (250 MHz, CDCl₃) δ8.58 (1H, d), 8.10 (1H, s), 7.99 (1H, d), 7.31(1H, dd), 7.19 (1H, d), 6.83 (1H, s), 4.33 (2H, m), 4.28 (2H, m), 3.95(3H,s), 3.88 (1H, m), 3.84 (2H, s), 3.24 (2H, m), 3.12 (1H, m), 2.94(1H,m), 2.64 (3H, m), 2.33 (1H, m), 2.21 (1H, m), 1.75 (2H, m). MS (ES) m/z469 (M+H)⁺

Example 34cis-4-[(2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-1-[2-(3-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-3-oldihydrochloride dihydrochloride Enantiomer 1 (a)cis-{1-[2-(3-Fluoro-6-methoxy-quinolin-4-yl)-ethyl]-3-hydroxy-piperidin-4-yl)-carbamicacid tert-butyl ester enantiomer 1

This was prepared from the vinyl quinoline (31e) (0.50 g) andcis-4-tert-butoxycarbonylamino-3-hydroxy-piperidine enantiomer 1,prepared from the benzyl carbamate (5b, enantiomer1) (0.53 g,) by themethod of Example 5(c), were heated with dimethylformamide (0.6 mL) and1,1,5,5-tetramethylguanidine (2 drops) at 100-105° C. for 72 h. Work upas for Example (31f) followed by chromatography on silica (0-4%methanol/dichloromethane) gave an oil (0.44 g), plus some recoveredvinyl compound (90 mg). MS (ES) m/z 420 (M+H)⁺

(b)cis-4-Amino-1-[2-(3-chloro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-3-olenantiomer 1

The tert-butyl carbamate (34a) was deprotected by the method of Example(31g) to give the crude amine (0.37 g). MS (ES) m/z 320 (M+H)⁺

(c) Title Compound

The crude amine (34b) (0.34 g) was reacted with aldehyde (2c) (0.167 g)in dry chloroform (3 mL) and methanol (3 mL) under reflux for 4 h, with3 A molecular sieves. The mixture was cooled, treated with sodiumtriacetoxyborohydride (0.642 g) and stirred at room temperature over 2days, then the mixture was washed with aqueous sodium carbonate and theaqueous phase was re-extracted with 10% methanol/chloroform and thecombined organics were dried and evaporated. Chromatography on silica(DCM then 2-10% methanol/dichloromethane) gave the free-base of thetitle compound (0.42 g).

¹H NMR (400 MHz, CDCl₃) δ8.59 (1H, s), 8.10 (1H, s), 7.98 (1H, d), 7.32(1H, dd), 7.20 (1H, d), 6.83 (1H, s), 4.32 (2H, m), 4.28 (2H, m), 3.97(3H,s), 3.90 (1H, br s), 3.84 (2H, s), 3.25 (2H, t), 3.12 (1H, m),2.95(1H, m), 2.55-2.70 (3H, m), 2.33 (1H, d), 2.23 (1H, m), 1.77 (2H,m). MS (ES) m/z 469 (M+H)⁺

The free base in dichloromethane was treated with an excess of HCl (4Min 1,4-dioxan), followed by evaporation of solvent and trituration withether to give the title compound (0.49 g).

Example 35{1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxyethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amineDihydrochloride Enantiomer 1 (a)7-Chloro-2-methoxy-8-oxiranyl-[1,5]naphthyridine Enantiomer 1 andEnantiomer 2

The racemic oxirane (1e) (3.55 g) was subjected to preparative HPLC on aChiralpak AD 20 um column (77 mm×250 mm) eluting with 90:10hexane:ethanol (isocratic) (flow rate 280 mL/min) to afford thefast-running isomer (Enantiomer 1) (1.67 g; 99% ee; retention time 9.4min.) and the slow running enantiomer (Enantiomer 2) (1.62 g; 97% ee;retention time 12.9 min.).

(b){1-[(2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester Enantiomer 1

A mixture of epoxide (35a; enantiomer 1) (0.813 g) andpiperidin-4-yl-carbamic acid tert-butyl ester (0.69 g) was heated in DMF(5 drops) at 100° C. for 6 hr. The product was dissolved in chloroformand chromatographed on silica gel (methanol-DCM) to afford the solidproduct (1.0 g) containing ca. 20% of the epoxide ‘wrong-opening’isomer.

(c)1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-piperidin-4-ylamineEnantiomer 1

The ester (35b) (0.69 g) was deprotected by the method of Example (31g)to give a foam (0.68 g) containing ca. 20% of the ‘epoxidewrong-opening’ isomer.

(d) Title Compound

The amine (35c) (0.68 g) and aldehyde (2c) (0.334 g) were heated inchloroform (4 mL) and methanol (4 mL) with 3 A molecular sieves for 1.5hr at 80° C., cooled, and treated with sodium triacetoxyborohydride(1.28 g) and the mixture was stirred overnight at room temperature.Chloroform was added and the mixture was filtered, treated with sodiumcarbonate solution and extracted with methanol-chloroform, dried (sodiumsulfate), evaporated and chromatographed on silica gel (methanol-DCM) toafford the free base of the title compound (0.65 g), containing ca 20%of the epoxide ‘wrong-opening’ isomer

LC-MS (ES) m/z 486/488 (M+H)⁺ (2 peaks with retention time 1.13 and 1.23min.)

¹H NMR δH (CDCl₃, 400 MHz), 1.40-1.70 (2H, m), 1.88 (2H, br. d), 2.25(2H, q), 2.52 (1H, m), 2.65 (1H, dd), 3.00 (2H, m), 3.10 (1H, dd), 3.80(2H, s), 4.05 (3H, s), 4.25-4.35 (4H, m), 5.67 (1H, m), 6.38 (1H, brs),6.83 (1H, s), 7.15 (1H, d), 8.05 (1H, s), 8.23 (1H, d), 8.70 (1H, s)(plus impurity peaks).

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wasrecrystallised several times (cold methanol), triturated with ether,filtered and dried under vacuum to provide the pure title compound (60mg), [LC-MS (ES) single peak with retention time 1.23 min.]

Example 366-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride Enantiomer 1

The amine (35c) (0.78 g) and aldehyde (7d) (0.45 g) were dissolved inDMF (2 mL), methanol (2 mL) and acetic acid (0.2 mL) and heated with 3 Amolecular sieves for 2 hr at 80° C., cooled, and treated with sodiumcyanoborohydride (0.44 g) and the mixture was stirred overnight at roomtemperature. Chloroform was added and the mixture was filtered, treatedwith sodium carbonate solution and extracted with methanol-chloroform,dried (sodium sulfate), evaporated and chromatographed on silica gel(methanol-DCM) to afford the free base of the title compound as a solid(0.64 g), containing 15-20% of the ‘epoxide wrong-opening’ isomer.

LC-MS (ES) m/z 499/501 (M+H)⁺ (2 peaks retention time 1.22 and 1.30min.)

¹H NMR δH (CDCl₃, 400 MHz), 1.40-1.70 (2H, m), 1.88 (2H, br. d), 2.25(2H, q), 2.52 (1H, m), 2.65 (1H, dd), 3.00 (2H, br t), 3.07 (1H, dd),3.80 (2H, s), 4.03 (3H, s), 4.65 (2H, s), 5.67 (1H, m), 6.42 (1H, br d),6.95 (1H, d), 7.15 (2H, 2×d), 8.21 (1H, d), 8.70 (1H, s).

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wasrecrystallised from methanol-water, washed with a small amount of waterthen ether, and dried under vacuum to provide the pure title compound[LC-MS (ES) single peak with retention time 1.30 min.].

Example 376-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride Enantiomer 2 (a){1-[(2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-piperidin-4-yl)-carbamicacid tert-butyl ester Enantiomer 2

This was prepared from a mixture of epoxide (35a Enantiomer 2) (0.74 g)and piperidin-4-yl-carbamic acid tert-butyl ester (0.63 g) by the methodof Example (35b) to afford the product (0.71 g) containing ca. 20% ofthe epoxide ‘wrong-opening’ isomer.

(b)1-[(2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-piperidin-4-ylamineEnantiomer 2

This was prepared from the ester (37a) (0.71 g) by the method of Example(35c) to give the product as an oil (0.52 g) containing ca. 20% of the‘epoxide wrong-opening’ isomer.

(c) Title Compound

This was prepared from the amine (37b) (0.52 g) and aldehyde (7d) (0.30g) by the method of Example (36c) to afford the free base of the titlecompound as a solid (0.42 g), containing 15-20% of the ‘epoxidewrong-opening’ isomer.

LC-MS (ES) m/z 499/501 (M+H)⁺ (2 peaks with retention time 1.22 and 1.30min.)

¹H NMR δH (CDCl₃, 400 MHz), 1.40-1.70 (2H, m), 1.88 (2H, br. d), 2.25(2H, q), 2.52 (1H, m), 2.65 (1H, dd), 3.00 (2H, br t), 3.07 (1H, dd),3.80 (2H, s), 4.03 (3H, s), 4.65 (2H, s), 5.67 (1H, m), 6.42 (1H, br d),6.95 (1H, d), 7.15 (2H, 2×d), 8.21 (1H, d), 8.70 (1H, s).

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wasrecrystallised from methanol-water, washed with a small amount of waterthen ether, and dried under vacuum to provide the pure title compound[LC-MS (ES) single peak with retention time 1.30 min.].

Example 38{6-(trans)-1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]-3-hydroxypiperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amineEnantiomer 2 (a)trans-4-amino-1-[2-(3-chloro-6-methoxyquinolin-4-yl)ethyl]piperidin-3-olenantiomer 2

This was prepared by hydrogenation of piperidine (17f, enantiomer 2) bythe method of Example (5c) followed by reaction with7-chloro-2-methoxy-8-vinyl-quinoline and removal of the Boc protectinggroup (see Example 5d-e) (0.055 g).

(b) Title Compound

This was prepared by the general procedure of Example (5f) from amine(38a) and 2,3-dihydro-[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde(Example 2c) and sodium borohydride, to give a yellow solid (0.0266 g,37%) following flash chromatography on silica gel (9:1 CHCl₃/MeOHcontaining 1% NH₄OH).

¹H NMR (400 MHz, d₄-MeOH) δ 8.59 (s, 1H), 8.02 (s, 1H), 7.92 (d, J=9 Hz,1H) 7.42 (m, 2H), 6.98 (s, 1H), 4.38 (m, 2H), 4.32 (m, 2H), 4.00 (s,3H), 3.88 (d, J=13.8 Hz, 1H), 3.75 (m, d, J=13.8 Hz, 1H), 3.55 (m, 1H),3.43 (t, J=8.2 Hz, 2H), 3.33 (m, 2H), 3.21 (m, 1H), 3.08 (m, 1H), 2.66(m, 2H), 2.38 (m, 1H), 2.12 (m, 3H), 1.48 (m, 1H). LC/MS (ES) m/z 485(M+H)⁺.

Example 39(trans)-6-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]-thiazin-3-oneDihydrochloride Enantiomer 2 (a)trans-{1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-yl)-carbamicacid tert-butyl ester Enantiomer 2

To a solution of 7-chloro-2-methoxy-8-vinyl-[1,5] naphthyridine (asprepared in Example (3a)) (1.14 g, 5.16 mmol) in anhydrous DMF (5 mL)was added trans-4-tert-butoxycarbonylamino-3-hydroxy-piperidineenantiomer 2 (1.2 g, 5.16 mmol) [prepared from Example (17f, enantiomer2) by hydrogenation]. After heating the mixture at 85° C. for 18 h, thereaction mixture was cooled to room temperature and concentrated invacuo. The crude product was purified by column chromatography on silicagel (gradient elution: 50% EtOAc/hexanes to 100% EtOAc) to afford anoff-white solid (1.1 g, 49%).

¹H NMR (400 MHz, CDCl₃) δ8.67 (s, 1H), 8.17 (d, 1H, J=9 Hz), 7.12 (d,1H, J=9 Hz), 4.63 (m, 1H), 4.09 (s, 3H), 3.74 (m, 1H), 3.52 (m, 4H),3.44 (m, 1H), 3.28 (m, 1H), 2.97 (m, 1H), 2.81 (m, 2H), 2.3 (m, 1H),2.24 (m, 1H), 1.96 (m, 1H), 1.47 (s, 9H); LC/MS (ES) m/z 437.4 (M+H)⁺.

(b)trans-4-Amino-1-[2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-3-olenantiomer 2 trihydrochloride

To a solution of carbamate (39a) (1.1 g, 2.52 mmol) in dichloromethane(15 mL) was added 4 N HCl in dioxane (6.3 mL, 25.2 mmol). After stirringfor 1 h, the reaction mixture was concentrated in vacuo to obtain a paleyellow solid (1 g, 89%) LC/MS (ES) m/z 337.4 (M+H)⁺.

(c) Title Compound

To a solution of amine (39b) (0.5 g, 1.12 mmol) in anhydrousdichloromethane (20 mL) and absolute ethanol (40 mL) was added3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (7d)(0.218 g, 1.12 mmol) and triethylamine (5.6 mmol, 0.780 mL). To thisreaction mixture was added anhydrous sodium sulfate and the reaction wasstirred at RT for 18 h under N₂, then sodium borohydride (43 mg, 1.12mmol) was added and stirring was continued for an additional 2 h. Thecrude product was filtered through a cake of Celite®, washing with 10%methanol/dichloromethane, and the filtrate was concentrated in vacuo.Purification by column chromatography on silica gel (10%methanol/dichloromethane containing 5% NH₄OH in methanol) gave the titlecompound (260 mg, 45%) as the free base. This was dissolved indichloromethane and 4 N HCl in dioxane (1.01 mmol, 0.252 mL) was added.The solid was triturated with diethyl ether and evaporated to dryness toafford the title compound (0.3 g, 45%) as a yellow solid:

¹H NMR (400 MHz, CD₃OD) δ8.67 (s, 1H), 8.15 (d, 1H, J=9 Hz), 7.66 (d,1H, J=7.8 Hz), 7.17 (d, 1H, J=9 Hz), 7.02 (d, 1H, J=7.8 Hz), 4.37 (m,3H), 4.09 (s, 3H), 3.86 (m, 2H), 3.73 (m, 2H), 3.52 (m, 1H), 3.43 (m,2H), 3.37 (m, 2H), 3.28 (m, 1H), 3.13 (m, 1H), 2.45 (m, 1H), 2.25 (m,1H). LC/MS (ES) m/z 515.4 (M+H)⁺.

Example 40trans-6-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one Trihydrochloride Enantiomer 2

To a solution of amine (39b) (0.499 g, 1.12 mmol) in anhydrousdichloromethane (20 mL) and absolute ethanol (40 mL) was added3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4] oxazine-6-carboxaldehyde (1l)(0.200 g, 1.12 mmol) and triethylamine (5.6 mmol, 0.780 mL). To thisreaction mixture was added anhydrous sodium sulfate and the reaction wasstirred at RT for 18 h under N₂, then sodium borohydride (44 mg, 1.12mmol) was added and stirring was continued for an additional 2 h. Thecrude product was filtered through a cake of Celite, washing with 10%methanol/dichloromethane, and the filtrate was concentrated in vacuo.Purification by column chromatography on silica gel (10%methanol/dichloromethane containing 5% NH₄OH in methanol) gave the titlecompound (130 mg, 23%) as the free base. This was dissolved indichloromethane and 4 N HCl in dioxane (0.782 mmol, 0.195 mL) was added.The solid was triturated with diethyl ether and evaporated to dryness toafford the title compound (25%) as an off-white solid:

¹H NMR (400 MHz, DMSO-d₆) δ 9.81 (s, 1H), 9.31 (s, 1H), 8.84 (s, 1H),8.33 (d, 1H, J=9 Hz), 7.46 (d, 1H, J=8.1Hz), 7.34 (d, 1H, J=9 Hz), 7.23(d, 1H, J=8.1 Hz), 4.70 (s, 2H), 4.38 (m, 7H), 4.12 (s, 3H), 3.81 (m,3H), 3.56 (m, 1H), 3.43 (m, 3H), 3.18 (m, 1H), 2.99 (m, 1H), 2.56 (m,1H), 2.18 (m, 1H). LC-MS (ES) m/z 499.4 (M+H)⁺.

Example 41trans-6-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl]ethyl}-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one dihydrochloride Enantiomer 1 (a)trans-4-Amino-1-[2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-3-olEnantiomer 1

To a solution of 7-chloro-2-methoxy-8-vinyl-[1,5] naphthyridine (3a)(1.2 g, 5.5 mmol) in anhydrous DMF (2.5 mL) was addedtrans-4-tert-butoxycarbonylamino-3-hydroxy-piperidine enantiomer 1 (1.2g, 5.5 mmol) [prepared from (17f, enantiomer 1) by hydrogenation]. Themixture was heated at 85° C. for 18 h, then was cooled to roomtemperature and concentrated in vacuo. To the crude product was addeddioxan (5 mL) followed by 4N HCl in dioxan (10 mL). After stirring for 1h, the reaction mixture was concentrated in vacuo. The crude product waspurified by flash chromatography on silica gel (gradient elution: 4%MeOH in CH₂Cl₂, then 90:10:1 CH₂Cl₂/MeOH/conc. NH₄OH, then 80:20:2CH₂Cl₂/MeOH/conc. NH₄OH) to afford an off-white solid (1.3 g, 71% fortwo steps). LC/MS (ES) m/z 337 (M+H)⁺.

(b) Title Compound

To a solution of amine (41a) (1.1 g, 3.9 mmol) in DMF (15 mL) containing4 A molecular sieves was added3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (7d)(0.64 g, 3.9 mmol). The mixture was stirred at RT under N₂ for 18 h,then was filtered. The filtrate was concentrated to dryness and theresidue was dissolved in MeOH (15 mL). Sodium borohydride (0.15 g, 3.9mmol) was added and the reaction mixture was stirred for an additional 2h. The solvent was evaporated and the residue was purified by columnchromatography on silica gel (gradient elution: 4% MeOH/CH₂C[2, then90:10:1 CH₂Cl₂/MeOH/conc. NH₄OH). Recrystallization of the purifiedproduct from MeOH/H₂O gave the free base of the title compound (1.1 g,54%). The title compound was obtained by adding 2 equivalents of 1N HClto a solution of the free base (0.90 g) in MeOH. Evaporation of thesolvent and drying in high vacuum @ 40° C. for 2-days, followed bytrituration with Et₂O, afforded the title compound as a yellow solid(0.90 g). LC/MS (ES) m/z 515 (M+H)⁺.

Example 426-({(3R,4r,5S)-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3,5-dihydroxy-piperidin-4-ylamino)}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-onedihydrochloride (a) (+/−)(1R,5S,6S)-5-Hydroxy-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acidbenzyl ester

To a solution of (+/−) 3-hydroxy-3,6-dihydro-2H-pyridine-1-carboxylicacid benzyl ester (Heterocycles 1992, 33, 349, or Synthesis 2000, 521;1.4 g, 6.0 mmol) in CH₂Cl₂ (25 mL) at 0° C. was added MCPBA (60% byweight, 1.7 g, 6.0 mmol).

After stirring at this temperature for 18 h, the reaction mixture waspoured into a solution of saturated Na₂CO₃ and extracted with EtOAc(2×). The combined extracts were washed with brine, dried (MgSO₄), andconcentrated to afford a clear oil (quantitative yield). LC/MS (ES) m/z250 (M+H)⁺.

(b) (3S,4r,5R)-4-Azido-3,5-dihydroxy-piperidine-1-carboxylic acid benzylester

To a solution of (+/−)(1R,5S,6S)-5-hydroxy-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acidbenzyl ester (1.6 g, 6.4 mmol) in DMF (25 mL) containing LiClO₄ (0.76 g,7.1 mmol) was added NaN₃ (0.46 g, 7.1 mmol). The reaction mixture washeated at 80° C. for 1 h then the solvent was evaporated. The residuewas purified by flash chromatography on silica gel (gradient elution:33% EtOAc/hexanes then 50% EtOAc/hexanes) to afford a white solid (0.70g, 37%).

¹H NMR (MeOH-d₄): δ 7.26-7.18 (m, 5H), 5.01 (s, 3H), 4.09-4.06 (m, 2H),3.26-3.20 (m, 2H), 3.04 (dd, 1H, J=9.4, 3.4); COSY45 showed that onlythe methines on carbon bearing oxygen correlated to the methylenesindicating epoxide opening as indicated.

(c) (3S,4r,5R)-4-Amino-3,5-dihydroxy-piperidine-1-carboxylic acid benzylester

To a degassed solution of(3S,4r,5R)-4-azido-3,5-dihydroxy-piperidine-1-carboxylic acid ethylester (0.50 g, 1.7 mmol) in EtOAc (50 mL) was added 5% Pd/C(Degussa-type, 0.10 g). After stirring under hydrogen (1 atm) for 18 h,the reaction mixture was degassed and filtered through Celite®, and thefiltrate was concentrated to afford a clear oil, which was used in thenext step without purification. LC/MS (ES) m/z 267 (M+H)⁺.

(d)(3S,4r,5R)-4-tert-Butyloxycarbonylamino-3,5-dihydroxy-piperidine-1-carboxylicacid benzyl ester

To a solution of amine (42c) (1.7 mmol) in EtOAc (25 mL) at RT was addeddi-tert-butyl dicarbonate After stirring at RT for 18 h, the reactionwas concentrated and the residue was triturated with Et₂O to afford awhite solid (0.42 g, 68% for two steps).

(e) ((3S,4r,5R)-3,5-Dihydroxy-piperidin-4-yl}carbamic acid tert-butylester

To a degassed solution of benzyl ester (42d) (0.32 g, 0.87 mmol) in MeOH(15 mL) was added 20% Pd(OH)₂/C (0.030 g). After stirring under hydrogen(1 atm) for 18 h, the reaction mixture was degassed and filtered throughCelite®, and the filtrate was concentrated to afford a clear oil (0.17g, 84%). LC/MS (ES) m/z 267 (M+H)⁺.

(f)(3R,4r,5S)-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3,5-dihydroxy-piperidin-4-yl}-carbamicacid tert-butyl ester

To a solution of 7-chloro-2-methoxy-8-vinyl-quinoline (4c) (0.10 g, 0.45mmol) in DMF (2.5 mL) was added piperidine (42e) (0.094 g, 0.45 mmol).After heating to 100° C. for 4 days, the reaction was concentrated andthe residue was purified by flash chromatography on silica gel (4%MeOH/CH₂Cl₂) to afford an oil (0.055 g, 27%).

(g)(3R,4r,5S)-4-Amino-1-[2-(3-chloro-6-methoxy-quinol-4-yl)-ethyl]-piperidine-3,5-dioltrihydrochloride

To a solution of ester (42f) (0.055 g, 0.12 mmol) in dioxan (5.0 mL) wasadded 4 N HCl in dioxan (5 mL). After stirring at RT for 2.5 h, thereaction was concentrated. The residue was subjected to high vacuum at40° C. for 18 h to afford a yellow solid, which was used in the nextstep without purification.

(h) Title Compound

To a solution of amine (42g) (0.12 mmol) in DMF (2.5 mL) containingCs₂CO₃ (0.098 g, 0.30 mmol) and 4 A molecular sieves was added3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (1l)(0.026 g, 0.13 mmol). The reaction was stirred at RT for 18 h, then thesolvent was evaporated. MeOH (10 mL) was added to the residue, followedby NaBH₄ (0.049 g, 0.13 mmol). The reaction mixture was stirred at RTfor 1 h and then concentrated. The residue was purified by flashchromatography on silica gel (gradient elution: 4% MeOH/CH₂Cl₂, then 10%MeOH/CH₂Cl₂, then 90:10:1 CH₂Cl₂/MeOH/conc. NH₄OH). Fractions containingonly the desired product were combined and concentrated, and the residuewas dissolved in MeOH containing 1N HCl. The solvent was evaporated andthe residue was triturated with Et₂O to afford the title compound (0.010g, 14% over three steps) as a light-yellow solid.

¹H NMR (MeOH-d₄): δ 8.49 (s, 1H); 7.82 (d, 1H, J=9.1Hz), 7.34-7.28 (m,2H), 7.15 (d, 1H, J=8.0 Hz), 6.86 (d, 1H, J=8.0 Hz); 4.53 (s, 2H), 3.95(s, 2H), 3.50 (m, 2H); 3.35 (m, 2H,), 3.04 (dd, 2H, J=10.7, 4.0 Hz),2.62 (m, 2H), 2.24 (t, 1H, J=9.4 Hz); 2.03 (t, 2H, J=10.5 Hz). LC/MS(ES) m/z 514 (M+H)⁺.

Example 436-({1-[2-(3-Fluoro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one dihydrochloride)

This compound was prepared from amine crude amine (31g), prepared from1.84 mmol carbamate (31h), and aldehyde (1l) (0.32 g, 1.80 mmol) by themethod of Example (31f). Chromatography on silica (5-15%methanol/dichloromethane) gave the free-base (0.77 g, 90%).

¹H NMR (250 MHz, CDCl₃) δ8.58 (1H, d), 7.99 (1H, d), 7.30 (1H,d), 7.25(1H, d), 7.20 (1H, d), 6.92 (1H, d), 4.62 (2H, s), 3.96 (3H, s), 3.84(2H, s), 3.31 (2H, m), 3.12 (2H, m), 2.73 (2H, m), 2.66 (1H, m), 2.34(2H, m), 2.00 (2H, m), 1.65 (2H, m). MS (ES) m/z 466 (M+H)⁺

The free base in dichloromethane/methanol was treated with 2 equivalentsof HCl (4M in 1,4-dioxan), followed by evaporation of solvent andtrituration with ether to give the title compound.

Example 44{1-[2-(3-Bromo-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amineDihydrochloride (a) 3-Bromo-6-methoxy-quinolin-4-ol

6-Methoxy-quinolin-4-ol (4.0 g) in acetic acid (65 mL) was treated withN-bromosuccinimide (4.5 g) and the mixture was heated at 35° C. for 4hr, cooled, and the solid collected and dried in vacuo to give a solid(4.0 g).

MS (ES) m/z 255/257 (M+H)⁺.

(b) 1,1,1-Trifluoro-methanesulfonic acid 3-bromo-6-methoxy-quinolin-4-ylester

Dry DMF (25 mL) was added to a suspension of 60% sodium hydride in oil(0.47 g). It was cooled to 0° C., the phenol (44a) (2.0 g) was added andthe mixture was stirred for 15 min. N-phenyltrifluoromethanesulphonimide(3.0 g) was added and the mixture was allowed to stir at roomtemperature overnight. It was evaporated, and chromatographed on silicagel (petroleum ether/DCM) and washed with sodium bicarbonate solution,dried (magnesium sulfate) and evaporated to give a solid (1.95 g). MS(+ve ion electrospray) m/z 387/389 (MH+).

(c) 3-Bromo-6-methoxy-4-vinyl-quinoline

This was prepared from the triflate (44b) (0.40 g) to give a solid (0.20g) by the method of Example (4c), heating for 2 hr at 100° C. MS (ES)m/z 264/266 (M+H)⁺.

(d){1-[2-(3-Bromo-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert butyl ester

A mixture of the vinyl-quinoline (44c) (0.20 g) andpiperidin-4-yl-carbamic acid tert-butyl ester (0.152 g) in chloroform(0.35 mL) was heated at 100° C. for 4 days, then the product wasdissolved in DCM and chromatographed on silica gel (methanol-EtOAc) toafford the solid product (0.23 g). MS (ES) m/z 464/466 (M+H)⁺.

(e) 1-[2-(3-Bromo-6-methoxy-quinolin-4-yl}-ethyl]-piperidin-4-ylamine

The ester (44d) (0.23 g) was dissolved in chloroform (6 mL) andtrifluoroacetic acid (6 mL) and the solution was stirred at roomtemperature for 0.5 hr then evaporated to dryness, basified (sodiumbicarbonate) and the solid product collected, washed with water anddried in vacuo. MS (ES) m/z 364/366 (M+H)⁺.

(f) Title Compound

The amine (44e) (0.158 g) and aldehyde (2c) (0.72 g) were dissolved inchloroform (3 mL) and methanol (3 mL) with 3 A molecular sieves andheated at 70° C. for 2 hr., cooled and sodium triacetoxyborohydride(0.27 g) was added and the solution was stirred overnight at roomtemperature. The mixture was filtered and evaporated, re-dissolved inDCM and chromatographed on silica gel (methanol-ammonia-EtOAc) to affordthe free base of the title compound as a solid (0.13 g). MS (ES) m/z513/515 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 4M HCl in dioxan and evaporated to dryness. The solid wastriturated with ether to give the title compound (0.07 g).

Example 45cis-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-4-[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-piperidin-3-olDihydrochloride Enantiomer 1

A solution ofcis-4-amino-1-[2-(3-chloro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-3-olenantiomer 1 [(5e; free base) prepared from (5d) by reaction withtrifluoroacetic acid/DCM followed by a basic work-up] (229 mg) andcarboxaldehyde (2c) (0.113 g) in DMF (7 mL) was treated with sodiumtriacetoxyborohydride (0.45 g) portionwise and the mixture was stirredat room temperature overnight. It was quenched with 2N HCl, basifiedwith sodium bicarbonate and extracted with 5% methanol-DCM, dried(magnesium sulfate), evaporated and purified by silica gelchromatography eluting with EtOAc:MeOH:NH₄OH_((aq)) and then bypreparative HPLC (to remove a small quantity of bis-alkylated material)to afford the free base of the title compound.

This material was converted to the title compound (100 mg) by dissolvingin chloroform and adding 2 equivalents of 1M HCl/ether then evaporatingto dryness.

¹H NMR δH (250 MHz, CD₃OD) 8.96 (1H, s), 8.36 (1H, s), 8.10 (1H, d),7.55 (2H, m), 7.35 (1H, d), 4.60 (1H, m), 4.50 (2H, m), 4.45 (2H, s),4.40 (2H, m), 4.10(3H, s), 4.00-3.85 (4H, m), 3.75 (1H, m), 3.50-3.30(4H, m), 2.55-2.30 (2H, m).

MS (ES) m/z 485/487 (M+H)⁺.

Example 46cis-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-4-[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-piperidin-3-olDihydrochloride Enantiomer 2

This was prepared fromcis-4-amino-1-[2-(3-chloro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-3-olenantiomer 2 (243 mg) [(prepared fromcis-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester enantiomer 2 (5b) by the methods described for Example 45]to give, after silica gel chromatography the free base of the titlecompound.

This material was converted to the title compound (120 mg) by dissolvingin chloroform and adding 2 equivalents of 1M HCl/ether then evaporatingto dryness.

¹H NMR δH (250 MHz, (CD₃)₂SO)

8.74 (1H, s), 8.22 (1H, s), 8.00 (1H, d), 7.60 (1H, d), 7.50 (1H, dd),7.00 (1H, s), 6.56 (1H, brs), 4.45 (1H, m), 4.40 (2H, m), 4.32 (2H, m),4.25 (2H, m), 4.05 (3H, s), 3.90-3.50 (5H, m), 3.40-3.05 (4H, m),2.30-2.10 (2H, m). MS (ES) m/z 485/487 (M+H)⁺.

Example 471-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinaminedihydrochloride (a) 3-fluoro-4-nitrophenyl methyl ether

A solution of 3-fluoro-4-nitrophenol (25 g, 0.159 mmol) in acetonitrile(500 mL) and methanol (500 mL) was treated with diisopropyl ethylamine(28 mL). The reaction mixture was cooled in an ice-bath and after 30minutes, trimethylsilyidiazomethane was added dropwise. The mixture wasstirred at room temperature for 18 hours then evaporated under vacuum toafford the product as an oil (29.4 g, 100%). MS (+ve ion electrospray)m/z 172 (MH+).

(b) 2-fluoro-4-(methoxy)aniline

A solution of (a) (28.1 g, 164 mmol) in ethanol (200 mL) washydrogenated with palladium on charcoal. The reaction mixture wasfiltered through Kieselguhr and evaporated under vacuum to afford theproduct as an oil (22.8 g, 98%).

MS (+ve ion electrospray) m/z 141 (MH+).

(c) ethyl 8-fluoro-6-(methoxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylate

A mixture of aniline (b) (22.8 g, 162 mmol) and diethyl[(ethyloxy)methylidene]propanedioate (32.6 mL) were heated to reflux inDowtherm A under a flow of argon. After 15 minutes (when all ethanol wasremoved), the mixture was allowed to cool down and was diluted withpentane. A precipitate was formed which was triturated with pentane,filtered and dried under vacuum to afford the product as an oil (33.06g, 77%).

MS (+ve ion electrospray) m/z 265 (MH+).

(d) ethyl 4-bromo-8-fluoro-6-(methoxy)-3-quinolinecarboxylate

To a solution of quinolone (c) (12 g, 45 mmol) in DMF (56 ml) was addeddropwise phosphorus tribromide (4.5 ml, 47 mmol) over fifteen minutes(slightly exothermic). The reaction was held at 0° C., with an ice bath,for one hour and allowed to warm to room temperature then stirred for afurther 2 hours. The mixture was then diluted with water (400 mL). Asolution of sodium bicarbonate was added to reach pH 7. The reactionmixture was stirred for one hour at 0° C. then filtered. The precipitatewas washed with water and dried in vacuo to afford the product as ayellow solid (12.2 g, 82%).

MS (+ve ion electrospray) m/z 329 (MH+).

(e) 4-bromo-8-fluoro-6-(methoxy)-3-quinolinecarboxylic acid

A solution of bromide (d) (12.2 g, 37.3 mmol) in tetrahydrofuran (450mL) was diluted by addition of a solution of sodium hydroxide 2N (27 mL)in water (75 mL). The reaction mixture was stirred overnight at roomtemperature then acidified to pH 3 with a solution of hydrogen chloride5N. The solvents were evaporated to half the volume in vacuo. Thereaction mixture was acidified to pH 1 by further addition of hydrogenchloride 5N, cooled to 4° C. for 30 minutes then filtered. Theprecipitate was dried in vacuo to afford the product as a white solid(10.1 g, 90%).

MS (+ve ion electrospray) m/z 301 (MH+).

(f) 1,1-dimethylethyl[4-bromo-8-fluoro-6-(methoxy)-3-quinolinyl]carbamate

A solution of carboxylic acid (e) (7.5 g, 25 mmol) in butanol (40 mL)and DMF (88 mL) was treated with triethylamine (30 mL) thendiphenylphosphoryl azide (5.8 mL, 27.5 mmol). The reaction mixture washeated at 100° C. for two hours under argon atmosphere. The mixture wasthen cooled down to room temperature and evaporated to half the volumein vacuo. Water (100 mL) was added to the mixture under vigorousstirring. A precipitate was formed, filtered and dried in vacuo. Thiscrude product was chromatographed on silica gel eluting with 10%methanol in dichloromethane to afford the product as a white solid (6.4g, 69%).

MS (+ve ion electrospray) m/z 372 (MH+).

(g) 4-bromo-8-fluoro-6-(methoxy)-3-quinolinamine

Carbamate (f) (6.4 g, 17.3 mmol)) was treated with trifluoroacetic acid(50 ml) in dichloromethane (50 ml) at room temperature for two hoursthen evaporated to dryness. The residue was basified with sodiumbicarbonate. A precipitate was formed which was filtered and dried invacuo to afford the product as a white solid (4.7 g, 100%). MS (+ve ionelectrospray) m/z 272 (MH+).

(h) 4-bromo-6-methoxy-8-fluoroquinolin-3-yl-diazonium tetrafluoroborate

A solution of quinolinamine (g) (3 g, 11.1 mmol) in anhydrous THF (40mL) cooled down to −9° C., with an ethanol/ice bath, was treated withnitrosonium tetrafluoroborate (1.4 g, 12.2 mmol) added portionwise over20 minutes. The reaction mixture was stirred for 30 minutes at −2° C.under argon atmosphere. A precipitate was formed which was filtered,washed with cold THF and dried in vacuo overnight to afford the productas a yellow solid (3.2 g, 79%). MS (+ve ion electrospray) m/z 370 (MH+).

(i) 4-bromo-3,8-difluoro-6-(methoxy)quinoline

Diazonium salt (h) (2.4 g, 6.5 mmol) was added to hot Decalin® (45 mL).The reaction mixture was maintained at 170° C. for 5 minutes. ColdDecalin® (20 mL) was added and the reaction mixture was cooled down withan ice bath. The Decalin® layer was decanted off the dark residue andwashed with a solution of sodium bicarbonate, brine and water. Theorganic layer was dried over magnesium sulfate. Solvents from thework-up were evaporated under vacuum and and the Decalin® layer wascooled down to 4° C. A precipitate was formed (product) which wasfiltered off. The decalin filtrate and the dark residue obtained beforework-up were combined and chromatographed eluting with dichloromethaneto afford the further product as a white solid (combined yield, 0.75 g,42%). MS (+ve ion electrospray) m/z 275 (MH+).

(j) 4-ethenyl-3,8-difluoro-6-(methoxy)quinoline

Bromide (i) (0.63 g, 2.3 mmol) in DME (26 mL) under argon, was treatedwith tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.115 mmol) andthe mixture stirred at room temperature for 20 minutes. Anhydrouspotassium carbonate (0.32 g, 2.3 mmol), water (7 mL), andvinylborane:pyridine complex (see F. Kerins and D O'Shea J. Org. Chem.2002, 67, 4968-4971) (0.22 g, 0.92 mmol) were added and the mixture washeated at 100° C. for 2 hr. It was cooled, diluted with water andextracted with ether, dried over magnesium sulfate and evaporated todryness. After work-up the product was chromatographed on silica gel,eluting with 10% methanol in DCM to afford a white solid (0.46 g, 90%).MS (+ve ion electrospray) m/z 221 (MH+).

(k) 1,1-dimethylethyl(1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)carbamate

A mixture of the vinyl-quinoline 0) (0.46 g, 2.08 mmol),piperidin-4-yl-carbamic acid tert-butyl ester (0.62 g, 3.12 mmol) in DMF(0.7 mL) and tetramethylguanidine (5 drops) was heated at 100° C. for 18hours. It was cooled, diluted with water and extracted with ethylacetate, dried over magnesium sulfate and evaporated to dryness. Afterwork-up the product was chromatographed on silica gel, eluting withmethanol-DCM to afford the desired product as a white solid (0.5 g,62%). MS (+ve ion electrospray) m/z 421 (MH+).

(l) 1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinamine

The carbamate (k) (0.5 g, 1.3 mmol)) was treated with trifluoroaceticacid (14 ml) in dichloromethane (14 ml) at room temperature for twohours then evaporated to dryness. The residue was basified to pH 8 withsodium bicarbonate and extracted several times with a solution of 10%methanol in dichloromethane. The combined organic layers were dried overmagnesium sulfate and evaporated to dryness to afford the product as awhite solid (0.4 g, 100%). MS (+ve ion electrospray) m/z 321 (MH+).

(m) Title Compound

The amine (I) (0.43 g, 1.35 mmol) and aldehyde (2c) (0.22 g, 1.35 mmol)were dissolved in DMF (14 mL) and sodium triacetoxyborohydride (0.87 g,4.05 mmol) added. The solution was stirred overnight at roomtemperature. The reaction mixture was quenched with 2N HCl, basifiedwith sodium bicarbonate solution, and extracted with 5% methanol indichloromethane. The residue was chromatographed eluting with 0-10%methanol in dichloromethane to afford the free base of the product as awhite solid (0.23 g, 37%).

¹H NMR δH (d4-MeOD) 8.57 (1H, s), 8.00 (1H, s), 7.23 (1H, dd), 7.15 (1H,dd), 6.96 (1H, s), 4.31 (4H, m), 3.98 (3H, s), 3.79 (2H, s), 3.10 (2H,m), 2.65 (2H, m), 2.62 (1H, m), 2.19 (2H, m), 1.96 (2H, m), 1.51 (2H,m). MS (+ve ion electrospray) m/z 471 (MH+).

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound.

The following examples were prepared by analogous method to Example 47,using the aldehyde shown:

Example 48 7-{[(1-{2-[3,8-Difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-onedihydrochloride

Preparation of 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carbaldehyde

(a) 6-Methoxycarbonylmethylsulfanyl-5-nitro-nicotinic acid methyl esterA solution of 6-chloro-5-nitro-nicotinic acid methyl ester (1.0 g)[prepared as described by A. H. Berrie et al. J. Chem. Soc. 2590-2594(1951)] in dichloromethane (10 mL) containing triethylamine (0.76 mL)was treated with mercapto-acetic acid methyl ester (0.44 mL) and thesolution was stirred at room temperature for 1 hour and evaporated todryness. Sodium bicarbonate solution was added and the mixture wasextracted with dichloromethane, dried (anhydrous sodium sulfate) andevaporated to afford a solid (1.0 g). MS (+ve ion electrospray) m/z 287(MH+). (b) 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxylicacid methyl ester The ester (a) (1.0 g) in acetic acid (50 mL) wastreated with iron powder (10 g) and the mixture was stirred and heatedat 60° C. for 1 hour, cooled and filtered. The filtrate was evaporated,treated with sodium bicarbonate solution and extracted with warmchloroform, It was dried (anhydrous sodium sulfate) and evaporated togive a white solid (0.85 g). MS (+ve ion electrospray) m/z 225 (MH+).(c) 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxylic acid Asolution of ester (b) (2.8 g) in dioxan was treated dropwise withaqueous sodium hydroxide then acidified with 2 M HCl. After partialevaporation, a precipitate was formed, filtered and dried under vacuumto afford the product as a solid (2.5 g) MS (−ve ion electrospray) m/z209 (M − H⁻). (d) 7-Hydroxymethyl-1H-pyrido[2,3-b][1,4]thiazin-2-one Thecarboxylic acid (c) (2.48 g) in THF with triethylamine was cooled to−10° C. and isobutylchloroformate was added. After 20 minutes thesuspension was filtered through Kieselguhr into an ice- cooled solutionof sodium borohydride in water. The mixture was stirred 30 minutes andthe pH reduced to 7 with dilute HCl. The solvents were evaporated andthe residue triturated under water. The product was filtered and driedunder vacuum to afford a solid (1.3 g), after recrystallisation fromchloroform-methanol (9:1). MS (+ve ion electrospray) m/z 197 (MH+). (e)2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxaldehyde Asolution of alcohol (d) (1.22 g) was oxidised with manganese dioxide bythe method of Example (2c) to afford a solid (0.7 g). MS (−ve ionelectrospray) m/z 193 (M − H⁻). 496-{[(1-(2-[3,8-Difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedinydrochloride

Aldehyde is 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde as in example (1l) 506-{[(1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[a,2-b][1,4]thiazin-3(4H)-onedihydrochloride

Aldehyde is 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde as in example (7d) 511-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-([1,3]dioxolo[4,5-c]pyridin-6-ylmethyl)-4- piperidinaminedihydrochloride

1,3-benzodioxole-5-carbaldehyde is commercially available

Example 52{1-[2-(9-Chloro-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-aminedihydrochloride (a) 7-Bromo-2,3-dihydro-benzo[1,4]dioxin-6-ylamine

A solution of 2,3-dihydro-benzo[1,4]dioxin-6-ylamine (80g) intetrahydrofuran (1 litre) at −78° C. was treated with concentratedsulfuric acid (80 drops) then N-bromosuccinimide was added over 0.5hour. After the addition the mixture was stirred at −78° C. for 1 hourthen treated with solid sodium carbonate (12g). The mixture wasevaporated and the residue partitioned between ether and water. Theorganic extract was dried, filtered and evaporated to give to an oilthat was chromatographed on silica gel eluting with dichloromethane toafford an oil (141 g, 92%). MS (+ve ion electrospray) m/z 231 (MH+).

(b)5-[(7-Bromo-2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione

A mixture of aniline (a) (14.8 g, 64.3 mmol), triethyl orthoformate(12.7 mL, 77.2 mmol) and 2,2-dimethyl-[1,3]dioxane-4,6-dione (Meldrum'sacid) (11.1 g, 77.2 mmol) in ethanol (70 mL) was heated to reflux. After1 hour the mixture was allowed to cool to room temperature thenfiltered, washing with ethanol then ether, to afford a white solid (22.9g, 93%). MS (+ve ion electrospray) m/z 385 (MH+).

(c) 6-Bromo-2,3-dihydro-7H-[1,4]dioxino[2,3-f]quinolin-10-one

Enamine (b) (22.9 g) was added portionwise to refluxing Dowtherm A® (45mL) over 3 minutes. After a further 3 minutes at reflux the mixture wascooled to room temperature. Ethyl acetate/hexane (10 mL/20 mL) was addedand a black solid isolated by filtration. This residue was dissolved inhot methanol (400 mL) and filtered through Keiselguhr. Water (800 mL)was added and the mixture stored at 5° C. overnight. Filtration anddrying afforded a pale yellow solid (10.3 g, 61%). MS (APCl⁻) m/z 281[M−H]

(d) 2,3-Dihydro-7H-[1,4]dioxino[2,3-f]quinolin-10-one

A suspension of (c) (3.4 g, 12 mmol) in water/dioxan (150 mL/80 mL) wastreated with 1M aqueous sodium hydroxide solution then hydrogenated over10% palladium on charcoal (1.5 g) for 20 hours. The mixture was filteredthen acidified with 5M aqueous hydrochloric acid. On concentrating to ca100 mL, a solid began to crystallise out. The mixture was stored at 5°C. overnight. Filtration and drying afforded a pale yellow solid (2.8 g,100%). MS (APCl⁻) m/z 202 [M−H]-(e)9-Chloro-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-ol

The quinolone (d) (5.05 g) in acetic acid (70 mL) was sonicated andwarmed until all had dissolved, and then it was treated withN-chlorosuccinimide (3.64 g) and the mixture was heated at 35° C. for 18hr, cooled and the solid collected and washed with acetic acid and driedin vacuo at 40° C. overnight, to give a white solid (1.65 g). MS (ES)m/z 238/240 (M+H)⁺

(f) 10-Bromo-9-chloro-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

The quinolin-4-ol (e) in dry DMF (8 mL) was cooled in ice and phosphorustribromide (0.7 mL) added drop-wise, and the mixture was stirred, withice-cooling for 30 minutes then allowed to warm to room temperature andstirred for a further 2 hours. It was cooled in ice and sodium carbonatesolution was added and the solid was collected, washed well with water,and dried in vacuo, to afford a pale yellow solid (1.65 g). MS (ES) m/z301/303/304 (M+H)⁺.

(g) 9-Chloro-10-vinyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

The bromide (f) (1.65 g) in DME (60 mL) under argon, was treated withtetrakis(triphenylphosphine)palladium(0) (0.32 g) and the mixturestirred at room temperature for 20 minutes. Anhydrous potassiumcarbonate (0.76 g), water (18 mL), and vinylborane:pyridine complex (seeF. Kerins and D O'Shea J. Org. Chem. 2002, 67, 4968-4971) was added andthe mixture was heated at 100° C. for 2 hr. It was cooled, diluted withwater and extracted with ether, dried (magnesium sulfate) and evaporatedto dryness. After work-up the product was chromatographed on silica gel,eluting with methanol-DCM, to afford a white solid (1.35 g).

MS (ES) m/z 248/250 (M+H)⁺.

(h){1-[2-(9-Chloro-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

A mixture of the vinyl-quinoline (g) (680 mg) andpiperidin-4-yl-carbamic acid tert-butyl ester (815.mg) in DMF (0.9 mL)and tetramethylguanidine (5 drops) was heated at 100° C. for 18 hours.It was cooled, diluted with water and extracted with ethyl acetate,dried (magnesium sulfate) and evaporated to dryness. After work-up theproduct was chromatographed on silica gel, eluting with methanol-DCM toafford the desired product (0.82 g). MS (ES) m/z 448 (M+H)⁺.

(i)1-[2-(9-Chloro-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-ethyl]-piperidin-4-ylamine

The carbamate (h) (0.82 g) in DCM (21 mL) was treated with TFA (21 mL)at room temperature for 1 hr and evaporated. Water and sodium carbonatewere added and the solution was extracted with 10% methanol in ethylacetate, dried (magnesium sulfate) and evaporated to afford the product(0.53 g). MS (ES) m/z 348 (M+H)⁺.

(j) Title Compound

The amine (i) (0.53 g) and aldehyde (2c) (0.25 g) were dissolved in DMF(16 mL) and sodium triacetoxyborohydride (0.96 g) added and the solutionwas stirred overnight at room temperature. The reaction mixture wasquenched with 2N HCl, basified with sodium bicarbonate solution, andextracted with methanol-DCM to afford the free base of the titlecompound (0.25 g).

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound (0.33 g).

¹H NMR of the hydrochloride salt δH (d6-DMSO) 9.60 (2H, bs), 8.73 (1H,s), 8.20 (1H, s), 7.60 (1H, d), 7.45 (1H, d), 7.20 (1H, s), 4.50 (2H,m), 4.40 (4H, m), 4.32 (2H, m), 4.25 (2H, m), 3.90-3.70 (3H, m),3.40-3.10 (6H, m), 2.35-2.05 (4H, m)

MS (+ve ion electrospray) m/z 497 (MH+).

Example 53(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinaminedihydrochloride (a) 2-[(6-Methoxypyridin-3-ylamino)-methylene]-malonicacid diethyl ester

5-Amino-2-methoxypyridine (100 g, 0.806 mole) in ethanol (1 litre) wastreated with diethyl ethoxymethylenemalonate (Aldrich) (163 ml, 1equivalent), refluxed 4 hours and cooled. The solvent was evaporated todryness to afford the product (238 g, quantitative). MS (ES) m/z 295(M+H)⁺.

(b) 6-Methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acidethyl ester

Dowtherm A® (500 ml) in a 2 litre 3-neck flask fitted with still-headand condenser was brought just to boiling using an isomantle. Ester (a)(100 g) was added portionwise over 5 minutes and the solution boiled afurther 10-15 minutes, allowing some solvent to distil over. Thesolution was cooled to room temperature, stirred and treated withn-pentane (750 ml) and cooled in ice for 1 hour. The brown solid wasfiltered off, washed with n-pentane and dried under vacuum to give theproduct (61.72 g, 73%). MS (ES) m/z 249 (M+H)⁺.

(c) 4-Bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester

A suspension of6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethylester (b) (74.57 g, 300 mmole) in dry DMF (260 ml) under argon wasstirred efficiently in a water bath. Phosphorus tribromide (30.0 ml, 316mmole, 1.05 equiv.) was added dropwise over 15 minutes, stirringcontinued for 30 minutes and water (1 litre) added, followed bysaturated sodium carbonate solution to pH7. The solid was filtered off,washed with water and dried under vacuum over phosphorus pentoxide togive product (83.56 g, 90%). MS (ES) m/z 312 (M+H)⁺.

(d) 4-Bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic acid

A solution of 4-bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic acidethyl ester (2c) (83.56 g, 268 mmole) in tetrahydrofuran (835 ml) wasstirred and treated dropwise with 2N sodium hydroxide solution (300 ml,600 mmole) over 30 minutes. Stirring was continued overnight. 2N HCl wasadded to pH6 and the THF was evaporated under vacuum. 2N HCl was thenadded to pH2, followed by 250 ml of water and the mixture wasice-cooled. The solid was filtered off, washed with water and driedunder vacuum over phosphorus pentoxide to give product (76.7 g, slightlyover quantitative, presumed to contain a small amount of inorganics, butused in this state). MS (ES) m/z 284 (M+H)⁺.

(e) 4-Bromo-6-methoxy-[1,5]naphthyridin-3-ylamine

A suspension of 4-bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic acid(d) (50 g, 177 mmole) in dry DMF (600 ml) was treated with triethylamine(222.5 ml), t-butanol (265 ml) and diphenylphosphoryl azide (41.75 ml,194 mmole, 1.1 equiv.) and stirred under argon at 100° C. for 1 hour.The mixture was cooled and evaporated to low volume. Ethyl acetate andexcess aqueous sodium bicarbonate solution were added, shaken and someinsoluble solid filtered off. The layers were separated, the organicwashed twice with water and dried over magnesium sulfate. Evaporation todryness gave a crude mixture of4-bromo-6-methoxy-[1,5]naphthyridin-3-ylamine (minor product) and(4-bromo-6-methoxy-[1,5]naphthyridin-3-ylamine)carbamic acid t-butylester (major product) along with impurities.

This mixture was dissolved in dichloromethane (150 ml) and treated withtrifluoroacetic acid (100 ml), stirred 3 hours and evaporated. Theresidue was partitioned between chloroform and saturated sodiumbicarbonate solution, the layers separated and the aqueous re-extractedwith chloroform. The combined organic was dried over magnesium sulfateand evaporated to low volume. The solid was filtered, washed with asmall volume of chloroform and dried under vacuum (31.14 g, clean byNMR). The filtrate was applied to a silica column and eluted with 30%ethyl acetate/chloroform to obtain futher material (2.93 g). (Totalyield of product 34.07 g, 76%). MS (ES) m/z 255 (M+H)⁺.

(f) 8-bromo-2-methoxy-1,5-naphthyridin-7-yl-diazonium tetrafluoroborate

A solution of aminonaphthyridine (e) (50.4 g, 198 mmol) in dry THF (800mL) was stirred under argon atmosphere and maintained at −10° C.Nitrosonium tetrafluoroborate (26 g, 222 mmol) was added portionwiseover one hour and the resulting supsension stirred a further 30 minutes.After completion of the reaction, the suspension was filtered cold, thesolid washed with cold THF (250 mL) and dried under vacuum to afford theproduct (45.2 g, 65%). MS (ES) m/z 255 (M+H)⁺.

(g) 8-bromo-7-fluoro-2-(methoxy)-1,5-naphthyridine

A suspension of diazonium fluoroborate (f) (40.7 g, 115 mmol in decalin(750 mL) was stirred well and heated in an oil bath until decompositionwas complete. On completion (about 2 minutes), the reaction mixture wasremoved from heat and cooled in an ice/water bath. Chloroform (750 mL)was added to keep the product in solution. A black solid was formedwhich was triturated and sonicated for 30 minutes then chromatographedon a silica gel column eluting with 5% ethyl acetate in dichloromethaneto obtain the product as a yellow solid (16.8 g, 57%).

MS (ES) m/z 258 (M+H)⁺.

(h) 8-ethenyl-7-fluoro-2-(methoxy)-1,5-naphthyridine

Bromide (g) (10 g) in DME (310 mL) under argon, was treated withtetrakis(triphenylphosphine)palladium(0) (2.26 g, 0.05 eq) and themixture stirred at room temperature for 20 minutes. Anhydrous potassiumcarbonate (5.37 g, 1 eq), water, and vinylborane:pyridine complex (seeF. Kerins and D O'Shea J. Org. Chem. 2002, 67, 4968-4971) (5.85 g, 0.5eq) was added and the mixture was heated at 80° C. for 4 hours. Furthertetrakis(triphenylphosphine)palladium(0) (0.045 g), anhydrous potassiumcarbonate (0.54 g) and vinylborane:pyridine complex (0.6 g) were addedand the reaction mixture was stirred at 80° C. for a further 4 hours. Itwas cooled, diluted with ethyl acetate, washed with a solution of sodiumbicarbonate, dried over magnesium sulfate and evaporated to dryness. Theresidue was chromatographed on silica gel, eluting with 6% ethyl acetatein hexane to afford a white solid (6.4 g, 80%). MS (ES) m/z 205 (M+H)⁺.

(i)1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinamine

A mixture of the vinyl-naphthyridine (h) (1 g, 5 mmol) andpiperidin-4-yl-carbamic acid tert-butyl ester (1.3 g, 6.5 mmol) in DMF(6 mL) was heated at 105° C. for 22 hours, then at 110° C. for a further7 hours. It was cooled, evaporated to dryness and chromatographed onsilica gel, eluting with methanol-chloroform to afford the desiredproduct as an oil.

The oil was redissolved in dichloromethane (30 mL) and the solution wastreated with TFA (24 mL) and stirred at room temperature for 30 minutes.Solvents were evaporated under vacuum. Water and sodium carbonate wereadded and the solution was extracted with 15% methanol in chloroform,dried (magnesium sulfate) and evaporated to afford the product (390 mg,59% over two steps). MS (ES) m/z 304 (M+H)⁺.

(j) Title Compound

The amine (i) (0.45 g, 1.48 mmol) and aldehyde (2c) (0.24 g, 1.48 mmol)were dissolved in a mixture of chloroform (8 mL) and methanol (8 mL) inthe presence of 3 A molecular sieves. The mixture was stirred at 70° C.for 4 hours cooled down and sodium triacetoxyborohydride (0.63 g, 2.96mmol) was added. The reaction mixture was stirred overnight at roomtemperature. It was then filtered through Kieselguhr and partitionedbetween sodium bicarbonate and 10% methanol in chloroform. The organiclayer was dried over magnesium sulfate, evaporated under vacuum and theresidue was chromatographed eluting with chloroform/methanol/NH₄OH toafford the free base of the product as a white solid (0.61 g, 91%).

1H NMR δH(CDCl₃) 8.56 (1H, s), 8.16 (1H, d), 8.10 (1H, s), 7.06 (1H, d),6.84 (1H, s), 4.20-4.35 (4H, m), 4.08 (3H, s), 3.80 (2H, s), 3.35-3.42(2H, m), 3.00-3.06 (2H, m), 2.70-2.75 (2H, m), 2.45-2.55 (1H, m), 2.18(2H, bt), 1.92 (2H, bd), 1.47 (2H, bq). MS (ES) m/z 454 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound.

The following examples were prepared by analogous methods to Example 53,using the aldehydes shown:

Example 54N-(2,3-Dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinaminedihydrochloride

Preparation of 2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazine-7- carbaldehyde

(a) 5-Fluoro-2-picoline N-oxide Preparation of 5-fluoro-2-picoline wasbased on E. J. Blanz, F. A. French, J. R. DoAmaral and D. A. French, J.Med. Chem. 1970, 13, 1124-1130. 5-Amino-2-picoline (12.5 g) in ethanol(105 ml) and 50% fluoroboric acid (44.5 ml) was stirred at −5° C. andtreated dropwise over 45 minutes with n-butyl nitrite (31.25 ml). Thesolution was maintained at this temperature for 3 hours, treated withether (100 ml, precooled to −20° C.) and the solid filtered off, quicklytransferred to a flask and covered with hexane (precooled to −20° C.).After allowing to warm to approx. 20° C. and standing for 3 days thehexane was decanted and 2 M NaOH solution added until basic (pH10). Themixture was filtered and the filtrate extracted with dichloromethane (10× 200 ml). The organic solution was dried, evaporated to 200 ml andtreated with m-chloroperbenzoic acid (26.5 g). After stirring 16 hoursthe solution was washed with excess aqueous sodium bicarbonate and theaqueous re-extracted with dichloromethane (10 × 200 ml). The organic wasdried and evaporated and the residue chromatographed (15% EtOH/EtOAc) togive title compound (5.5 g). MS (APCl⁺) m/z 128 (MH⁺, 100%) (b)5-Fluoro-4-nitro-2-picoline N-oxide N-oxide (a) (2.12 g) was treatedwith an ice-cooled mixture of fuming nitric acid (7.1 ml) and conc.sulfuric acid (7.1 ml), heated at 35-40° C. for 1 hour and 65-70° C. for5.5 hours, cooled and ice (45 g) added. 10 M NaOH was added to pH10 andthe mixture extracted with EtOAc (3 × 30 ml). The oganic was dried andevaporated to give title compound as a yellow solid (2.16 g). MS (APCl⁺)m/z 173 (MH⁺, 30%), 127 (100%) (c)5-Ethoxycarbonylmethylthio-4-nitro-2-picoline N-oxide Ethylmercaptoacetate (1.51 g) in dioxan (15.6 ml) under argon was treatedwith sodium hydride (550 mg of a 60% dispersion in oil) and stirred for1 hour. 5-Fluoro-4-nitro-2- picoline N-oxide (2.16 g) was added andstirring continued 3 days. Water (50 ml) was added and the mixtureextracted with chloroform (3 × 50 ml). The organic was dried andevaporated to give a yellow solid (3.31 g). MS (APCl⁺) m/z 273 (MH⁺,80%), 125 (100%) d)2-Acetoxymethyl-5-ethoxycarbonylmethylthio-4-nitropyridine N-oxide (C)(3.31 g) in acetic anhydride (43 ml) was heated to 80° C. for 6 hours,evaporated, xylene (100 ml) added and evaporated. Chromatography of theresidue (eluent EtOAc/hexane 1:1) gave title compound (1.03 g). (e)7-Acetoxymethyl-2-oxo-2,3-dihydro-1H-pyrido[3,4- b][1,4]thiazineNitropyridine (d) (1.03 g) in glacial acetic acid (27.5 ml) was treatedwith iron powder (1.75 g), stirred at 60° C. for 3 hours, filteredthrough kieselguhr and evaporated to dryness. Saturated aqueous sodiumbicarbonate (300 ml) was added and extracted with EtOAc (3 × 200 ml),the organic was dried and evaporated. The residue was redissolved inacetic acid (30 ml), heated to 100° C. for 24 hours, evaporated andchromatographed (eluent EtOAc/hexane 1:1) to give title compound (340mg). MS (APCl⁻) m/z 237 ([M − H]⁻, 90%), 195 (100%) (f)7-Hydroxymethyl-2-oxo-2,3-dihydro-1H-pyrido[3,4- b][1,4]thiazine Asolution of 7-acetoxymethyl-2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazine (e) (340 mg) in dioxan (9 ml) was treateddropwise over 2 hours with 0.5 M NaOH (3.7 ml), stirred 18 hours andevaporated. Water (10 ml) was added and the white solid filtered off,washed with water and dried under vacuum to give title compound (231mg). MS (APCl⁻) m/z 195 ([M − H]⁻, 100%) (g)2-Oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazine-7- carbaldehyde Amixture of alcohol (f) (226 mg), manganese dioxide (600 mg), THF (22.5ml) and 1,2-dichloroethane (22.5 ml) was heated at 65° C. for 18 hoursunder argon. Filtration through kieselguhr and evaporation of solventgave title compound as an off-white solid (173 mg). MS (APCl⁻) m/z 193([M − H]⁻, 100%) (h) 3,4-dihydro-2H-1,4-benzothiazin-6-ylmethanol Asuspension of carboxaldehyde (g) (600 mg, 3.08 mmol) in dry THF (35 mL)was treated with 1 M solution of lithium aluminium hydride in THF (9 mL,9 mmol). The mixture was refluxed for 5 hours under argon, cooled andtreated with water (0.34 mL), a 2 N solution of sodium hydroxide (0.64mL) and water again (0.72 mL). The reaction mixture was stirred for 15minutes at room temperature and filtered. The filtrate was evaported toafford the product (432 mg, 77%) MS (+ve ion electrospray) m/z 182(MH+). (i) 3,4-dihydro-2H-1,4-benzothiazine-6-carbaldehyde A solution ofalcohol (h) (382 mg, 2.1 mmol) in acetonitrile (25 mL) was treated with2-iodoxybenzoic acid (2 g) and heated at 80° C. for 2 hours. The mixturewas filtered hot. The precipitate was boiled in acetonitrile (25 mL) andfiltered. The combined filtrates were evaporated. The residue wassonicated in chloroform for 10 minutes chromatographed on a silica gelcolumn eluting with 50% chloroform in ethyl acetate to afford theproduct (153 mg, 40%). MS (+ve ion electrospray) m/z 180 (MH+). 556-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)- onedihydrochloride

Aldehyde is 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde as in example (1l) 567-{[(1-(2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)- onedihydrochloride

Aldehyde is 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carbaldehyde as in example 48 573-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl)-4-piperidinyl)amino]methyl}-8-hydroxy-1(2H)-isoquinolinone dihydrochloride

Preparation of 8-{[(methoxy)methyl]oxy}-1-oxo-1,2-dihydro-3-isoquinolinecarbaldehyde

(a) Ethyl 2-methoxymethoxy-6-methylbenzoic acid A solution of ethyl2-hydroxy-6-methylbenzoic acid (4.56 g, 25.3 mmol) anddiisopropylethylamine (13.2 mL, 76 mmol) in dry dichloromethane (30 mL)was cooled in an ice- bath. Chloromethyl methyl ether (3.83 mL, 50.6mmol) was added slowly and the mixture was allowed to stand at 0° C.,warming slowly to room temperature. After 36 hours a further portion ofchloromethyl methyl ether (1.9 mL) was added and the mixture was left atroom temperature overnight. The mixture was then washed with 10% citricacid, water and brine, dried and evaporated to give the title compound(6.34 g, 100%). MS (+ve ion electrospray) m/z 225 (MH+). (b)8-Methoxymethoxy-1-oxo-1H-isochromene-3-carboxylic acid ethyl estern-Butyllithium (1.6 M in hexanes, 16.0 mL, 25.5 mmol) was added to asolution of diisopropylamine (3.64 mL, 25.5 mmol) andN,N,N′,N′-tetramethylethylenediamine (4.01 mL, 25.5 mmol) in drytetrahydrofuran (36 mL) at −78° C. After 10 min a solution of the ester(a), (5.10 g, 22.8 mmol) in dry tetrahydrofuran (18 mL) was addeddropwise, keeping the internal temperature <−60° C. The deep redsolution was stirred at −78° C. for 40 min, then diethyl oxalate (3.10mL, 22.8 mmol) in tetrahydrofuran (18 mL) was added over 5 min. Themixture was stirred at −78° C. for 6.5 hours, then treated with 10%citric acid. After warming to room temperature the phases were separatedand the aqueous phase was extracted with ethyl acetate. The combinedorganic phases were washed with brine, dried and evaporated.Chromatography on silica gel (20-40% ethyl acetate/hexane) gave theproduct (2.05 g, 32%). MS (+ve ion electrospray) m/z 235 (loss ofmethoxymethyl from MH+). (c)8-Methoxymethoxy-1,2-dihydro-1-oxo-isoquinoline-3- carboxylic acid ethylester The isochromene (b), (2.04 g, 7.34 mmol) was heated under refluxwith ammonium acetate (4.99 g) in ethanol (200 mL) for 24 hours. Solventwas evaporated and the residue was dissolved in ethyl acetate and water.The aqueous phase was extracted with ethyl acetate and combined organicswere washed with water, dried and evaporated. Chromatography on silicagel (50-100% ethyl acetate/hexane) gave impure product and recoveredisochromene. The latter was treated again with ammonium acetate (1.3 g)in ref luxing ethanol (50 mL) for 48 hours, then worked up as before.The crude material was combined with the initial impure product forchromatography on silica gel (0-2% methanol/dichloromethane). Elutedmaterial was re-chromatographed (50-100% ethyl acetate/hexane) to givethe title compound (0.87 g, 42%). MS (+ve ion electrospray) m/z 278(MH+). (d) 8-Methoxymethoxy-3-hydroxymethyl-2H-isoquinolin-1-one Theester (c), (0.66 g, 2.38 mmol) and sodium borohydride (0.14 g, 3.6 mmol)were heated in refluxing tert- butanol (3 mL) while methanol (0.6 mL)was added over 1 hour. Heating was continued for 2 hours ,then thecooled mixture was partitioned between ethyl acetate and water. Theaqueous phase was re-extracted with ethyl acetate and the combinedorganics were washed with brine, dried and evaporated to give the titlecompound (0.51 g, 91%). MS (+ve ion electrospray) m/z 236 (MH+). (e)8-{[(methoxy)methyl]oxy}-1-oxo-1,2-dihydro-3- isoquinolinecarbaldehydeThe alcohol (d), (0.51 g, 2.17 mol) was stirred with manganese (IV)oxide (3.12 g) in 1:1 dichloromethane/tetrahydrofuran (40 mL) at roomtemperature for 5 hours. The mixture was filtered and evaporated to givethe aldehyde (0.32 g, 63%). MS (−ve ion electrospray) m/z 232 (M − H⁻).After the reductive alkylation, the methoxymethyl protecting group wasremoved (to liberate the free phenol) with aqueous hydrochloricacid/dioxan, in quantitative yield giving the free base of the titlecompound 58 3-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-5H-pyridazino[3,4-b][1,4]thiazin-6(7H)-one dihydrochloride

Preparation of 6-oxo-6,7-dihydro-5H-pyridazino[3,4-b][1,4]thiazine-3-carbaldehyde

(a) 4-Amino-3,6-dichloropyridazine A suspension of3,4,6-trichloropyridazine (prepared by the method of B. Kasnar et al,Nucleosides and Nucleotides, 1994, 13, 459) (10.0 g) in conc. aqueousammonia (1L) was heated at 75° C. for 16 h. The mixture was concentratedto a small volume and extracted several times with ethyl acetate. Theextracts were washed with brine, dried and evaporated. The crude productwas recrystallised from ethyl acetate to give the title compound (5.03g) (b) 3-Chloro-6-oxo-6,7-dihydro-5H-pyridazino[3,4- b][1,4]thiazine Toa well-stirred suspension of sodium hydride (60% in mineral oil, 0.35 g,8.5 mmol) in anhydrous dimethylformamide (10 mL) at 0° C. was addedmethyl mercaptoacetate (0.70 mL, 7.9 mmol). After stirring at thistemperature for 20 min, a solution of 4-amino-3,6-dichloropyridazine(a), (1.29 g, 7.87 mmol) in dimethylformamide (10 mL) was added. Themixture was stirred at room temperature for 16 h, then most of thesolvent was removed in vacuo. The residue was diluted with water, theprecipitate was filtered off, washed with water and dried.Chromatography on silica (0-2% methanol/dichloromethane) gave theproduct (0.21 g, 13%). MS (+ve ion electrospray) m/z 202/204 (MH⁺) (c)6-Oxo-3-vinyl-6,7-dihydro-5H-pyridazino[3,4-b][1,4]thiazine To a mixtureof pyridazinothiazine (b) (0.15 g, 0.75 mmol),bis(triphenylphosphine)palladium(II) chloride (84 mg, 0.12 mmol) andlithium chloride (63 mg, 1.2 mmol) in dimethylformamide (3 mL) was addedtributyl(vinyl)tin (0.36 mL, 1.2 mmol). The mixture was heated at110-120° C. for 16 h, then evaporated. The residue was partitionedbetween water and ethyl acetate, the aqueous phase was extracted furtherwith ethyl acetate and the combined organics were dried and evaporated.Chromatography on silica (0-3% methanol/dichloromethane) gave theproduct (45 mg, 31%). MS (+ve ion electrospray) m/z 194 (MH⁺) (d)6-Oxo-6,7-dihydro-5H-pyridazino[3,4-b][1,4]thiazine-3- carboxaldehyde Toa suspension of vinyl compound (c) (0.65 g, 3.35 mmol) in 1,4-dioxan (60mL) was added osmium tetroxide (4% in water, 2 mL, 0.335 mmol), sodiumperiodate (1.43 g, 6.7 mmol) and water (20 mL). The mixture was stirredat room temperature for 7 h, then diluted with water and dichloromethaneand phases separated. The aqueous phase was extracted twice with 10%methanol/dichloromethane and the combined organics were dried andevaporated. Chromatography on silica (0-2% methanol/dichloromethane)gave the aldehyde (0.206 g), containing some of the corresponding methylhemiacetal. MS (+ve ion electrospray) m/z 196 (MH⁺). 596-{[(1-{2-[3-Fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one dihydrochloride

Aldehyde is 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde as in example (7d) 60N-(2,3-Dihydro[1,4]oxathiino[2,3-c]pyridin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinamine dihydrochloride

Preparation of 2,3-dihydro[1,4]oxathiino[2,3-c]pyridine-7- carbaldehyde

(a) 2-(hydroxymethyl)-5-({[4-(methoxy)phenyl]methyl}oxy)- 4(1H)-pyroneTo a solution of Kojic acid (50 g, 0.352 mol) in DMF (650 mL) under anargon atmosphere, cooled to 0° C., was added a solution of potassiumt-butoxide (39.5 g, 0.352 mol) in DMF (100 mL) and the resultantsuspension was vigourously stirred (overhead stirring) for 1 hour at5-10° C. 4-methoxybenzyl chloride was added dropwise and the mixture washeated to 50° C. for 30 hours, followed by 90° C. for 5 hours, afterwhich the mixture was evaporated to a minimum volume of DMF. 750 mL ofdistilled water was added and the mixture refridgerated overnight. Theresultant solid was collected by filtration and dried in vacuo at 50° C.to afford the product as a light brown solid (85 g, 64%). MS (+ve ionelectrospray) m/z 263 (MH+) (b)2-(hydroxymethyl)-5-({[4-(methoxy)phenyl]methyl}oxy) 4(1H)-pyridinone Toa suspension of pyrone (a) (40 g, 153 mmol) in ethanol (105 mL) wasadded concentrated aqueous ammonia (295 mL) and refluxed for 18 hours.The mixture was cooled, then refridgerated for 3 hours, and cooled in anice-bath for 45 minutes. The solid was filtered off, washed with coldethanol, follwed by cold petroleum ether and dried in vacuo to affordthe product as brown solid (26.21 g, 66%). (c)[5-({[4-(methoxy)phenyl]methyl}oxy)-4-oxo-1,4-dihydro-2-pyridinyl]methyl acetate A solution of pyridone (b) (26 g, 0.1 mol) inpyridine (150 mL) was cooled to 5° C. and treated with acetyl chloride(10.48 ml, 0.149 mol). The reaction mixture was stirred and allowed towarm to room temperature then heated at 60° C. for 18 hours. Pyridinewas evaporated under vacuum and the residue was triturated with water(250 mL), cooled in an ice- bath for 30 minutes. The solid formed wasfiltered off, washed with cold water and dried in vacuo to afford theproduct as a solid (15.7 g, 50%). MS (+ve ion electrospray) m/z 304(MH+). (d) (5-({[4-(methoxy)phenyl]methyl}oxy)-4-{[(trifluoromethyl)sulfonyl]oxy}-2-pyridinyl)methyl acetate Pyridone (c)(25 g, 82 mmol) was dissolved in dry dichloromethane (600 mL).Triethylamine (23 mL, 164 mmol) was added and the reaction cooled to 0°C. Trifluoromethane sulfonic anhydride (21 mL, 123 mmol) was addeddropwise and the reaction left to stir at room temperature overnight.The reaction was poured into water, the organic layer collected anddried (Mg SO₄). The crude product was chromatographed on silica elutingwith 10-20% Ethyl acetate in hexane. Product containing fractions werecombined and dried to afford the product as a solid (24.95 g, 70%). MS(+ve ion electrospray) m/z 436 (MH+). (e)[4-[(1,1-dimethylethyl)thio]-5-({[4-(methoxy)phenyl]methyl}oxy)-2-pyridinyl]methyl acetate To a solution oftriflate (d) (10 g, 23 mmol) in anhydrous toluene, (R)-(+)-2,2bis(diphenylphosphino)-1,1-binaphthyl (312 mg, 0.4 mmol) was added. Thereaction mixture was degassed before adding palladium acetate (103 mg,0.4 mmol). Sodium 2-methyl-2-propanethiolate was added, the systemdegassed again and the reaction mixture was strirred at 60° C. for 3hours, under argon atmosphere then at 70° C. for a further 18 hours. Thereaction mixture was filtered and the filtrate was evaporated undervacuum. The residue was partitioned between ethyl acetate and water. Theaqueous layer was extracted several times with ethyl acetate. Thecombined organic extracts were dried over magnesium sulfate andevaporated under vacuum. The residue was chromatographed on silica geleluting with 20-35% ethyl acetate in hexane to afford the product as anoil (9.1 g, 100%). MS (+ve ion electrospray) m/z 376 (MH+). (f)(4-[(1,1-dimethylethyl)thio]-5-hydroxy-2-pyridinyl}methyl acetate Asolution of (e) (9 g, 24 mmol) in dichloromethane (100 mL) was treatedwith triethylsilane (3.86 mL, 24 mmol). The reaction mixture was stirredfor 10 minutes before adding trifluoroacetic acid (10 mL). The reactionmixture was stirred at room temperature for 3 hours under argonatmosphere. The solvents were evaporated under vacuum. The residue wastaken up in dichloromethane and chromatographed on silica gel elutingwith 10%-30% ethyl acetate in hexane to afford the product as an oil(5.1 g, 83%). MS (+ve ion electrospray) m/z 256 (MH+). (g)6-(hydroxymethyl)-4-mercapto-3-pyridinol Acetate (f) (2.5 g, 9.8 mmol)was dissolved in concentrated HCl and the mixture was heated at 80° C.for 18 hours. The solvent was evaporated under vacuum and the residuewas triturated with diethyl ether to afford the product as a solid (1.35g, 88%). MS (+ve ion electrospray) m/z 158 (MH+). (h)2,3-dihydro[1,4]oxathiino[2,3-c]pyridin-7-ylmethanol To a solution ofmercaptopyridinol (g) (500 mg, 3.2 mmol) in anhydrous DMF, potassiumcarbonate was added. The reaction mixture was stirred for 10 minutes anddibromoethane (0.55 mL, 6.4 mmol) was added. The reaction mixture wasstirred at 70° C. for 18 hours under an argon atmosphere. DMF wasremoved in vacuo and the residue was partitioned between 5% MeOH indichloromethane and water. The aqueous layer was extracted several timeswith 5% methanol in dichloromethane. The combined organic extracts weredried over magnesium sulfate and evaporated under vacuum. The residuewas chromatographed on silica gel eluting with 3-5% methanol indichloromethane to afford the product as a solid (381 mg, 70%). MS (+veion electrospray) m/z 184 (MH+). (i)2,3-dihydro[1,4]oxathiino(2,3-c]pyridine-7-carbaldehyde Alcohol (h) wastreated with manganese (IV) oxide as in example (2c) to afford thealdehyde as a solid. MS (+ve ion electrospray) m/z 182 (MH+). 611-{2-[3-Fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-N-([1,3]oxathiolo[5,4-c]pyridin-6-ylmethyl)-4-piperidinaminedihydrochloride

[1,3]Oxathiolo[5,4-c]pyridine-6-carbaldehyde was prepared from Example(60 g) (6-(hydroxymethyl)-4-mercapto-3-pyridinol) by reaction withdibromomethane and oxidation to the aldehyde using the same methodologyas in Example (60).

Example 627-Fluoro-N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamidedihydrochloride (a) 6-Amino-5-bromo-3-fluoro-pyridine-2-carboxylic acidmethyl ester

A mixture of 6-amino-5-bromo-pyridine-2-carboxylic acid methyl ester(19.8 g) (T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633)and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (Selectfluor™), (34.3 g) in acetonitrile (340 ml)under argon was heated to 40° C. for 1 hour, 60° C. for 1 hour and then80° C. overnight. After partitioning between EtOAc and water (500 mleach) the aqueous fraction was re-extracted with EtOAc (300 ml) and thecombined organic solution dried with MgSO₄ and evaporated.Chromatography (20% then 30% EtOAc in hexane) afforded the product (2.09g).

MS (+ve ion electrospray) m/z 249 and 251 (MH⁺).

(b) 6-Amino-5-ethoxycarbonylmethylthio-3-fluoropyridine-2-carboxylicacid methyl ester

A solution of ethyl mercaptoacetate (1.15 ml) in DMF (40 ml) wasice-cooled under argon, treated with sodium hydride (420 mg of a 60%dispersion in oil) and stirred until all was in solution (about 1 hour).The ester (a) (2.48 g) was added, the mixture allowed to warm to roomtemp. and stirred overnight. EtOAc (150 ml) was added, the solutionwashed with water (3×150 ml), dried and evaporated. Chromatography ofthe residue (40% EtOAc in hexane) gave an oil (1.7 g). MS (+ve ionelectrospray) m/z 289 (MH⁺)

(c) Methyl7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate

A solution of the fluoropyridine (b) (1.7 g) in acetic acid (100 ml) washeated at 110° C. overnight, evaporated and dried under vacuum to givethe product as a white solid (1.5 g). MS (+ve ion electrospray) m/z 243(MH⁺).

(d)7-Fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid

This compound was prepared from the ester (c) by the method of Example(7b) (86%).

(e) Title Compound

A solution of carboxylic acid (d) (102 mg, 0.44 mmol) in THF (4 mL), at−15° C., under argon atmosphere, was treated with triethylamine (0.07mL, 0.53 mmol) then iso-butylchloroformate (0.06 mL, 0.49 mmol). Themixture was stirred at −15° C. for 15 minutes and filtered throughkieselguhr into a ice-cooled solution of amine (53i). The new reactionmixture was stirred for a further hour. Solvents were evaporated undervacuum and the residue was triturated under chloroform. The solid wasfiltered to afford the free base of the title compound as a solid (192mg, 84%)

1H NMR δH (d6-DMSO) 11.08 (1H, s), 8.76 (1H, s), 8.26 (1H, d), 8.19 (1H,d), 7.96 (1H, d), 7.23 (1H, d), 4.03 (3H, s), 3.65-3.75 (1H, m), 3.61(2H, s), 3.25-3.35 (2H, m, partly obscured by water), 2.93 (2H, bd),2.68 (2H, bt), 2.17 (2H, bt), 1.77 (2H, bd), 1.40 (2H, bq). MS (+ve ionelectrospray) m/z 515 (MH+).

This material was dissolved in chloroform/methanol and treated with anexcess of 1M HCl in ether then evaporated to dryness. The solid wastriturated with ether, filtered and dried under vacuum to provide thetitle compound.

The following examples were prepared by analogous methods to Example 62using the acids shown:

Example 63 N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide dihydrochloride

Acid is 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxylicacid as in example (48c) 64N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide

Acid is 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid as in example (7b) 65N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxamide

Preparation of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxylic acid

This acid was prepared from aldehyde (1l) (890 mg) by oxidation withOxone (potassium peroxymonosulphate) (3.1 g) in a DMF solution (50 mL).After 1.5 hours at room temperature, dilution with water (50 mL)filtration and drying in vacuo afforded the acid as a white solid (750mg, 77%). For this particular example, amide formation was accomplishedby dissolving the acid (26 mg) and amine (53i) (41 mg) in DMF (0.5 ml)then treating with triethylamine (27 mg) and HATU(O-(7-azabenzotriazol-1-yl)N,N,N′,N′,- tetramethyluroniumhexafluorophosphate) (56 mg). After 16 hours, dilution with water,filtration and drying in vacuc afforded the free base of the titlecompound (51 mg).

Example 66(3R,4S)-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinoldihydrochloride Enantiomer 1 (a) 1,1-dimethylethyl((3R,4S)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)carbamate

This was prepared by reaction of vinyl naphthyridine (53h) (1.42 g) andpiperidine (5c, Enantiomer1) (1.5 g) by heating in DMF (10 mL) with1,1,3,3-tetramethylguanidine (0.5 mL) at 90° C. for 32 hours.Evaporation and chromatography on silica eluting with 5% methanol indichloromethane afforded an oil (2.5 g). MS (ES) m/z 421 (M+H)⁺.

(b)(3R,4S)-4-amino-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinol

A solution of carbamate (a) (2.5 g) in dichloromethane (30 mL) wastreated with trifluoroacetic acid (25 mL) for 2 hours then evaporated todryness and triturated with ether. The resulting solid was partitionedbetween saturated aqueous potassium carbonate solution and 10%methanol/chloroform. The aqueous phase was extracted a further 6 timeswith 10% methanol/chloroform and the combined organic extracts weredried and evaporated to afford an oil (1.72 g). MS (ES) m/z 321 (M+H)⁺.

(c) Title Compound

The amine (b) (500 mg) and aldehyde (2c) (258 mg) were reacted togetherwith sodium triacetoxyborohydride as in example (53j) to afford the freebase of the title compound as a solid (420 mg, 55%).

1H NMR δH (CDCl₃) 8.61 (1H, s), 8.17 (1H, d), 8.10 (1H, s), 7.07 (1H,d), 6.84 (1H, s), 4.20-4.35 (4H, m), 4.08 (3H, s), 3.87 (1H, s), 3.83(2H, s), 3.39 (2H, bt), 3.10 (1H, bd), 2.95 (1H, bd), 2.78 (2H, bt),2.50-2.60 (1H, m), 2.34 (1H, d), 2.22 (1H, bt), 1.6-1.9 (m, includingwater). MS (+ve ion electrospray) m/z 470 (MH+).

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound.

The following examples were prepared by analogous method to Example 66using the aldehydes shown: Isomer E1

Example 67 6-{[((3R,4S)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2- b][1,4]thiazin-3(4H)-onedihydrochloride

Aldehyde is 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde as in example (7d) 686-{[((3R,4S)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2- b][1,4]oxazin-3(4H)-onedihydrochloride

Aldehyde is 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde as in example (1l)- 69(3R,4S)-4-[(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl)-3-piperidinoldihydrochloride

Aldehyde 2,3-dihydro[1,4]dioxino[2,3-b]pyridine-7-carbaldehyde wasprepared as described in Example (40e) of WO02056882.

Example 706-{[((3S,4R)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer 2— (a)(3S,4R)-4-amino-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinol

Vinyl-naphthyridine (53h) and piperidine (5c, Enantiomer 2) were reactedtogether and the adduct deprotected with trifluoroacetic acid as inExample (66a,b) to give an oil. MS (ES) m/z 321 (M+H)⁺.

(b) Title Compound

The amine (a) and aldehyde (7d) were treated as in example (66c) toafford the free base of the title compound in 64% yield.

1H NMR δH (CDCl₃) 8.61 (1H, s), 8.18 (1H, d), 7.55 (1H, d), 7.06 (1H,d), 6.99 (1H, d), 4.07 (3H, s), 3.92 (1H, bs), 3.87 (2H, ABq), 3.43 (2H,s), 3.37 (2H, t), 3.14 (1H, bd), 2.98 (1H, bd), 2.7-2.9 (2H, m),2.50-2.60 (1H, m), 2.34 (1H, d), 2.21 (1H, bt), 1.6-1.8 (2H, m). MS (+veion electrospray) m/z 499 (MH+).

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound (85 mg).

Example 71N-((3S,4R)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamidehydrochloride Enantiomer 2—

Carboxylic acid (7b) and amine (70a) were treated as in Example (62) toafford the desired amide in 51% yield.

1H NMR δH (CDCl₃) 8.64 (1H, s), 8.20 (2H, d), 7.98 (1H, d), 7.83 (1H,d), 7.76 (1H, d), 7.09 (1H, d), 4.09 (3H, s), 3.95-4.05 (1H, m), 3.82(1H, bs), 3.53 (2H, s), 3.39 (2H, t), 3.17 (1H, bd), 3.01 (1H, bd),2.7-2.9 (3H, m), 2.44 (1H, d), 2.29 (1H, bt), 1.8-1.9 (1H, m), 1.6-1.8(m, including water). MS (+ve ion electrospray) m/z 513 (MH+).

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The residue wastriturated with ether, filtered and dried under vacuum to provide thetitle compound as a pale yellow solid (55 mg).

Example 727-{[((3R,4S)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-onedihydrochloride Enantiomer 1 (a)(3S,4R)-4-amino-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinol

A mixture of vinyl-naphthyridine (47j) and piperidine (5c, Enantiomer 1)were reacted together and the adduct deprotected with trifluoroaceticacid as in Example (66a,b) to give an oil. MS (ES) m/z 338 (M+H)⁺.

(a) Title Compound

The amine (a) and the aldehyde from Example (48) were treated as inExample (66c) to afford the free base of the title compound in 19%yield.

1H NMR δH (CDCl3) 8.63 (1H, s), 8.15 (1H, d), 8.00 (1H, bs), 7.17 (1H,d), 7.05 (1H, dd), 6.96 (1H, d), 3.95 (3H, s), 3.90 (1H, m), 3.85 (1H,d), 3.78 (1H, d), 3.58 (2H, s), 3.20 (2H, m), 3.12 (1H, m), 2.95 (1H,m), 2.70 (2H, m), 2.50 (1H, m), 2.30 (1H, m), 2.20 (1H, m), 1.75 (2H,m). MS (+ve ion electrospray) m/z 516 (MH+).

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid (80 mg).

The following examples were prepared by analogous methods to Example 70using the aldehydes shown: Isomer E1

Exam- ple 73 6-{[((3R,4S)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4- piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one dihydrochloride Enantiomer 1

Aldehyde is 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde as in example (7d) 74(3R,4S)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3- piperidinoldihydrochloride dihydrochloride Enantiomer 1

Aldehyde is 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7- carbaldehyde as inexample(2c) 75 6-{[((3R,4S)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one dihydrochloride

Aldehyde is 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde as in example (1l)

Example 76 N-[(4-fluoro-1benzimidazol-2-yl)methyl]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinamine(a) 4-fluoro-1H-benzimidazole-2-carbaldehyde

Prepared from 4-fluoro-1H-benzoimidazole-2-ylmethanol, itself preparedfrom 3-fluoro-benzene-1,2-diamine by reaction with glycolic acid. MS(+ve ion electrospray) m/z 165 (MH+).

(b) Title Compound

Amine (31g) and the aldehyde (a) were reacted together with sodiumtriacetoxyborhydride as in Example (53j) to afford the free base of thetitle compound in 56% yield.

1H NMR δH (CDCl₃) 8.55 (1H, s), 7.98 (1H, d), 7.33 (1H, dd), 7.31 (1H,m), 7.23 (1H, d), 7.18 (1H, td), 6.95 (1H, dd), 4.10 (2H, s), 3.97 (3H,s), 3.25 (2H, m), 3.08 (2H, m), 2.62 (3H, m), 2.18 (2H, t), 1.99 (2H, brd), 1.50 (2H, qd). MS (+ve ion electrospray) m/z 513 (MH+).

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated with ether, filtered and dried under vacuum to provide thetitle compound.

The following examples were prepared by analogous methods to Example 76using the aldehydes shown:

Example 77 1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(1,5,6,7-tetrahydro-1,8-naphthyridin-2-ylmethyl)-4-piperidinamine dihydrochloride

1,5,6,7-tetrahydro-1,8-naphthyridine-2-carbaldehyde was preparedaccording to the procedure of WO 98/08840. 78N-(3-cinnolinylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinamine dihydrochloride

Preparation of 3-cinnolinecarbaldehyde

(a) 1-(3-cinnolinyl)-1,2,3,4-butanetetrol Anhydrous D-glucose (7.27 g,40.4 mmol) was added to a warm, stirred solution of phenylhydrazine(26.0 g, 240.7 mmol) in HCl/water. The mixture was heated to reflux. Aheavy yellow precipitate was formed and filtered after 2 hours thenwashed with warm water. The filtrate was cooled down to room temperatureand further yellow precipitate was formed, filtered off and combinedwith the first one. The filtrate was basified to pH 9 by addition ofdiluted sodium hydroxide. The aqueous layer was extracted several timeswith chloroform. Some precipitate was formed in the aqueous layer,filtered and washed with water then dried under vacuum. The filtrate washeated at 80° C. with charcoal for 30 minutes, filtered and evaporateduntil more precipitate was formed. The mixture was cooled in an ice-bathand the precipitate was collected, washed with chilled water and driedunder vacuum. The combined precipitates obtained after work-up affordthe desired product (1.94 g, 19%). MS (+ve ion electrospray) m/z 250(MH+). (b) 3-cinnolinecarbaldehyde A solution of (a) in hot water (200mL) was added to dioxan (150 mL). The solution was cooled to 20° C. thena solution of sodium periodate (6.46 g) in water (400 mL) was added. Themixture was stirred in the dark for 80 minutes. The aqueous wasextracted several times with diethyl ether. The aqueous was then saltedby addition of sodium chloride, extracted several times with diethylether then several times with ethyl acetate. The combined extracts weredried over magnesium sulfate and evaporated under vacuum to afford thealdehyde (1.29 g, 100%). MS (+ve ion electrospray) m/z 158 (MH+). 79N-(2,1,3-benzothiadiazol-5-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinamine dihydrochloride

Preparation of 2,1,3-benzothiadiazole-5-carbaldehyde

(a) Benzo[1,2,5]thiadiazol-5-yl-methanolBenzo[1,2,5]thiadiazole-5-carboxylic acid (2.00 g, 11.11 mmol) wasdissolved in tetrahydrofuran (50 mL) and cooled to 0° C. To this wasadded triethylamine (1.80 mL, 12.87 mmol) followed byisobutylchloroformate (1.62 mL, 12.40 mmol) in a dropwise manner. Theresulting slurry was stirred for a further 30 minutes at 0° C. and thenfiltered into a mixture of sodium borohydride (0.83 g, 21.84 mol) in icewater (20 mL). The resulting mixture was stirred at 0° C. for 30minutes, evaporated to one quarter of its volume and then extracted withdichloromethane (3 × 50 mL). The organic phases were combined and thendried over sodium sulfate. This was followed by concentration underreduced pressure to provide the desired product as a white solid whichwas used without further purification (1.50 g, 81%). MS (+ve ionelectrospray) m/z 167 (MH+). (b) 2,1,3-benzothiadiazole-5-carbaldehyde Astirred solution of alcohol (a) (3.5 g) in chloroform (150 mL) andtetrahydrofuran (300 mL) was treated with manganese dioxide (7.8 g) for18 hours and was filtered and evaporated to give the aldehyde as a whitesolid (2.5 g). MS (+ve ion electrospray) m/z 165 (MH+). 801-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-([1,3]thiazolo[5,4-b]pyridin-6-ylmethyl)-4-piperidinamine dihydrochloride

Preparation of [1,3]thiazolo[5,4-b]pyridine-6-carbaldehyde

(a) 5-Amino-6-thioxo-1,6-dihydro-pyridine-3-carboxylic acid methyl esterA mixture of sodium sulfide nonahydrate (2.17 g) and sulfur (0.29 g) washeated in boiling water (20 mL) until the solution was homogeneous andadded to a solution of 6-chloro-5-nitro-nicotinic acid methyl ester (3.1Og) in methanol (50 mL). The mixture was boiled for 15 minutes andcooled. The resulting disulfide was collected and washed with water togive a yellow solid (2.46 g). The solid (5 g) in acetic acid (100 mL)and 4 M HCl in dioxan (50 mL) was treated with zinc dust (12 g) and themixture was stirred at room temperature for 30 minutes, filtered andevaporated to dryness. Sodium acetate and sodium sulfate were added andthe mixture was extracted with warm chloroform and chromatographed onsilica gel, eluting with chloroform then methanol-chloroform to afford ayellow solid (2.3 g). MS (+ve ion electrospray) m/z 185 (MH+) (b)Thiazolo[5,4-b]pyridine-6-carboxylic acid methyl ester The amine (a)(0.7 g) was heated in formic acid (30 mL) under reflux for 30 minutesand was evaporated and chromatographed on silica gel (chloroform) togive a solid (0.65 g). MS (+ve ion electrospray) m/z 195 (MH+) (c)Thiazolo[5,4-b]pyridin-6-yl-methanol A solution of ester (b) (200 mg) indry tetrahydrofuran (15 mL) and dry diethyl ether (15 mL), cooled to−45° C., was treated with a 1 M solution of lithium aluminium hydride indiethyl ether (1.55 mL) and the mixture was heated under reflux for 18hours. It was cooled and an aqueous solution of saturated sodiumcarbonate was added cautiously. Dichloromethane and anhydrous sodiumsulfate were added and the mixture was stirred for 15 minutes andfiltered. The filtrate was evaporated to afford a white solid (95 mg).MS (+ve ion electrospray) m/z 167 (MH+) (d)[1,3]thiazolo[5,4-b]pyridine-6-carbaldehyde The alcohol (c) (65 mg) inchloroform (10 mL) was stirred with manganese dioxide (200 mg) for 5hours, filtered and evaporated and chromatographed on silica gel,eluting with dichloromethane then chloroform, to give a solid (65 mg).MS (+ve ion electrospray) m/z 165 (MH+). 81N-(3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinamine dihydrochloride

Preparation of 3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6- carbaldehyde

Prepared by reacting methyl 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate with lithium aluminium hydride followed byoxidation with manganese dioxide to give the carboxaldehyde. MS (+ve ionelectrospray) m/z 181 (MH+). 82N-(1,3-benzothiazol-5-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinamine dihydrochloride

Preparation of 1,3-benzothiazole-5-carbaldehyde

(a) Benzothiazol-5-ylcarboxylic acid 4-Chloro-3-nitrobenzoic acid (22 g,0.11 mol) was suspended in water, sodium hydroxide (4.33 g, 0.11 mol)and sodium sulfide hydrate (32 g) were added, and the mixture heated atreflux for 24 hours. After acidification with 5 M hydrochloric acid themixture was extracted with ethyl acetate. The extracts were dried overmagnesium sulfate and evaporated under reduced pressure. The productfrom this reaction (1 g, 5.9 mmol) was dissolved in formic acid andheated at reflux in the presence of zinc (0.1 g) for 6 hours. Themixture was allowed to cool and was concentrated under reduced pressure.The residue was diluted with water and neutralised with saturatedaqueous sodium hydrogen carbonate. Extraction with tetrahydrofuran andethyl acetate (1:1) gave a pale yellow solid (0.48 g) that was purifiedon silica gel using a methanol dichloromethane gradient. MS (+ve ionelectrospray) m/z 180 (MH+) (b) 1,3-benzothiazol-5-ylmethanol Acid (b)in tetrahydrofuran and triethylamine was cooled to 0° C. andisobutylchloroformate was added dropwise and the solution was stirred at0° C. for 2 hours, when it was filtered into a stirred solution ofsodium borohydride in ice/water. The mixture was stirred at 0° C. for 1hour and allowed to warm to room temperature. It was acidified with 2 Mhydrochloric acid, evaporated to half volume, and the resulting productwas collected, washed with water and dried in vacuo, to give a whitesolid. MS (+ve ion electrospray) m/z 166 (MH+). (c)1,3-benzothiazole-5-carbaldehyde Alcohol (b) was oxidised as in example(2c) to afford the product as a solid. MS (+ve ion electrospray) m/z 164(MH+). 831-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-([1,2,3]thiadiazolo[5,4-b]pyridin-6-ylmethyl)-4-piperidinamine dihydrochloride

Preparation of [1,2,3]thiadiazolo[5,4-b]pyridin-6-ylmethylmethanesulfonate

This intermediate was prepared from [1,2,3]thiadiazolo[5,4-b]pyridin-6-ylmethanol (prepared as in WO 2003064431) by reacting a THF solution ofthis alcohol with 1 equivalent each of triethylamine and methanesulfonylchloride. The solution of the resulting methanesulfonate was added to aDMF solution containing 1 equivalent of of amine (31 g) and potassiumcarbonate. Workup and chromatography afforded the free base of the titlecompound in 40% yield 847-{[(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)amino]methyl}1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one dihydrochloride

Aldehyde 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carbaldehydeis from example (48)- 85N-(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-7-ylmethyl)-1-(2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinaminedihydrochloride

2,3-dihydro[1,4]dioxino[2,3-b]pyridine-7-carbaldehyde was prepared asdescribed in Example (40e) of WO02056882 86N-(2,3-dihydro[1,4]oxathiino[2,3-c]pyridin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinamine dihydrochloride

The aldehyde 2,3-dihydro[1,4]oxathiino[2,3-c]pyridine-7-carbaldehyde wasprepared as in Example (60)

Example 874-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-methyl-4-piperidinecarboxamidedihydrochloride (a) 1-(1,1-dimethylethyl) 4-methyl4-amino-1,4-piperidinedicarboxylate

A suspension of 4-amino-1-{[(1,1-dimethylethyl)oxy]carbonyl}-4piperidinecarboxylic acid (4.3 g, 17.7 mmol) in acetonitrile/MeOH (20mL/2 mL) was treated with N-ethyl-N-(1-methylethyl)-2-propanamine (3.1mL, 18 mmol) followed by trimethylsilyidiazomethane (2M in hexane),(10.6 mL, 21.1 mmol). The reaction mixture was stirred at roomtemperature for 24 hours. A further 2 mL of trimethylsilyidiazomethanewas added and the mixture was stirred for a further 18 hours. Solventswere evaporated under vacuum. The residue was chromatographed on silicagel eluting with diethyl ether then ethyl acetate and 10% methanol inethyl acetate to afford the product as a white solid (2.95 g, 65%). MS(ES) m/z 259 (M+H)⁺.

(b) 1-(1,1-dimethylethyl) 4-methyl4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1,4-piperidinedicarboxylate

A mixture of amine (a) (2.44 g, 9.47 mmol), aldehyde (2c) (1.56 g, 9.52mmol), sodium triacetoxyborohydride (6.0 g, 28.5 mmol) and DMF (100 mL)was heated at 60° C. overnight. A further 0.8 g of aldehyde and 6.05 gof sodium triacetoxyborohydride were added and the stirring and heatingwere continued for a further 24 hours. DMF was evaporated under vacuum.The residue was dissolved in aqueous sodium bicarbonate and extractedseveral times with 10% MeOH in dichloromethane. The combined organicextracts were dried over magnesium sulfate and evaporated in vacuo. Thecrude was chromatographed on silica gel eluting with 2-5% MeOH indichloromethane to afford the product as an oil (4.4 g, 100%). MS (ES)m/z 408 (M+H)⁺.

(c)4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{[(1,1-dimethylethyl)oxy]carbonyl)-4-piperidinecarboxylicacid

A mixture of ester (b) (4 g, 9.8 mmol), 2M sodium hydroxide (10 mL, 20mmol), water (20 mL) and dioxan (100 mL) were heated under reflux for 3days. The mixture was filtered and evaporated under vacuum. The residuewas dissolved in a minimal amount of water and neutralised by dropwiseaddition of 5M HCl. A white precipitate was filtered off, washed withwater and dried in vacuo to afford the product (3.29 g, 76%). MS (ES)m/z 294 (M+H)⁺.

(d) 1,1-dimethylethyl4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-4-[(methylamino)carbonyl]-1-piperidinecarboxylate

A suspension of carboxylic acid (c) (0.98 g, 2.48 mmol) in DMF (35 mL)was treated with triethylamine (1.03 mL, 7.45 mmol),1-hydroxybenzotriazole (0.38 g, 2.53 mmol) and EDC (0.53 g, 2.7 mmol)and stirred at room temperature for 45 minutes. Methylamine (0.17 g, 2.5mmol) was added. The reaction mixture was stirred at room temperatureovernight. More triethylamine (0.21 mL), 1-hydroxybenzotriazole (0.08 g)and EDC (0.11 g) were added. The reaction mixture was stirred for 18hours. DMF was evaporated under vacuum. The residue was dissolved inwater and basified by addition of aqueous sodium carbonate. The aqueouslayer was extracted several times with dichloromethane/methanol. Thecombined organic were dried over magnesium sulfate and the residue waschromatographed on silica gel eluting with 2-5% MeOH in dichloromethaneto afford the product as an oil (0.9 g, 89%). MS (ES) m/z 407 (M+H)⁺.

(e)4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-N-methyl-4-piperidinecarboxamide

A solution of protected piperidine (d) (89 mg, 2.19 mmol) indichloromethane (10 mL) was treated with trifluoroacetic acid (10 mL).The mixture was stirred for 1.45 hours and evaporated under vacuum. Theresidue was triturated with diethyl ether, dissolved in 10% methanol indichloromethane and stirred with an excess of MP-carbonate resin(Argonaut Technologies, 2.54 mmol/g) for 3 hours. The resin was filteredoff and washed with methanol/dichloromethane then methanol alternately.The filtrate was evaporated under vacuum to afford the product as an oil(810 mg, quantitative). MS (ES) m/z 307 (M+H)⁺.

(f) Title Compound

A mixture of vinyl-quinoline (31e) and piperidine (e) was treated as inexample (52h) to afford the desired product in 49% yield.

1H NMR δH (CDCl₃) 8.59 (1H, s), 8.15 (1H, s), 7.98 (1H, d), 7.92 (1H,m), 7.30 (1H, dd), 7.22 (1H, d), 6.75 (1H, s), 4.33 (2H, m), 4.29 (2H,m), 3.96 (3H, s), 3.61 (2H, s), 3.26 (2H, m), 2.92 (2H, m), 2.81 (3H,d), 2.67 (2H, m), 2.34 (4H, m). MS (ES) m/z 510 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid (72 mg).

Example 884-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinecarboxamidedihydrochloride (a) 1,1-dimethylethyl4-(aminocarbonyl)-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinecarboxylate

A suspension of carboxylic acid (87c) (0.3 g, 0.76 mmol) in DMF (10 mL)was treated with triethylamine (0.21 mL, 1.52 mmol),1-hydroxybenzotriazole (0.1 g, 0.76 mmol) and EDC (0.16 g, 0.84 mmol)and stirred at room temperature for 30 minutes. Ammonia was bubbledthrough for a few minutes until all solid was dissolved. The reactionmixture was stirred at room temperature overnight. As the reaction hadnot gone to completion, more ammonia was bubbled through and thereaction mixture was stirred for a further 36 hours. The residualammonia was removed under vacuum and more triethylamine (0.21 mL, 1.52mmol), 1-hydroxybenzotriazole (0.1 g, 0.76 mmol) and EDC (0.16 g, 0.84mmol) were added. The reaction mixture was stirred for 2 hours andammonia was bubbled through for 10 minutes. The reaction mixture wasstirred overnight. DMF was evaporated under vacuum. The residue waspartitioned between diluted sodium hydroxide anddichloromethane/methanol. The aqueous layer was reextracted withdichloromethane/methanol. The combined organic extracts were washed withdiluted sodium hydroxide, dried over magnesium sulfate and the residuewas chromatographed on silica gel eluting with 0-5% MeOH in ethylacetate to afford the product as an oil (54 mg, 18%). MS (ES) m/z 393(M+H)⁺.

(b)4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-4-piperidinecarboxamide

A solution of protected piperidine (a) (54 mg, 0.14 mmol) indichloromethane (1 mL) was treated with trifluoroacetic acid (1 mL). Themixture was stirred for 1.5 hours and evaporated under vacuum. Theresidue was triturated with diethyl ether, dissolved in 10% methanol indichloromethane and stirred with 0.2 g of MP-carbonate resin (2.75mmol/g) for 3 hours. The resin was filtered off and washed withmethanol/dichloromethane then methanol alternately. The filtrate wasevaporated under vacuum to afford the product as an oil (501 mg,quantitative). MS (ES) m/z 293 (M+H)⁺.

(c) Title Compound

A mixture of vinyl-quinoline (31e) and piperidine (b) was treated as inexample (52h) to afford the desired product in 17% yield.

1H NMR δH (CDCl₃) 8.59 (1H, s), 8.12 (1H, s) 7.99 (1H, d), 7.72 (1H, brs), 7.30 (1H, dd), 7.22 (1H, d), 6.76 (1H, s), 5.38 (1H, br s), 4.32(2H, m), 4.28 (2H, m), 3.96 (3H, s), 3.67 (2H, s), 3.23 (2H, t), 2.89(2H, m), 2.68 (2H, m), 2.43 (2H, t), 2.27 (2H, td), 1.74 (2H, br d). MS(ES) m/z 496 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid (70 mg).

Example 894-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-N-methyl-4-piperidinecarboxamidedihydrochloride

A mixture of vinyl-naphthyridine (53h) and piperidine (87e) was treatedas in example (52h) to afford the desired product in 17% yield.

1H NMR δH (CDCl₃) 8.60 (1H, s), 8.17 (1H, d), 8.14 (1H, s), 7.88 (1H,m), 7.06 (1H, d), 6.74 (1H, s), 4.33 (2H, m), 4.29 (2H, m), 4.07 (3H,s), 3.60 (2H, s), 3.42 (2H, m), 2.94 (2H, m), 2.80 (3H, d), 2.75 (2H,m), 2.38 (2H, m), 2.25 (2H, m). MS (ES) m/z 511 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid (55 mg).

Example 904-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-(2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinecarboxamidedihydrochloride

A mixture of vinyl-naphthyridine (53h) and piperidine (88b) was treatedas in example (52h) to afford the desired product in 41% yield.

1H NMR δH (CDCl₃) 8.61 (1H, s), 8.17 (1H, d), 8.12 (1H, s), 7.70 (1H, brs), 7.06 (1H, d), 6.76 (1H, s), 5.28 (1H, br s), 4.33 (2H, m), 4.28 (2H,m), 4.08 (3H, s), 3.65 (2H, s), 3.41 (2H, t), 2.92 (2H, m), 2.78 (2H,m), 2.44 (2H, br), 2.25 (2H, m), 1.72 (2H, m). MS (ES) m/z 497 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid (62 mg).

Example 911-{2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-4-piperidinecarboxamidedihydrochloride

A mixture of vinyl-naphthyridine (3a) and piperidine (88b) was treatedas in example (52h) to afford the desired product in 53% yield.

1H NMR δH (CDCl₃) 8.65 (1H, s), 8.17 (1H, d), 8.14 (1H, s), 7.68 (1H, brs), 7.09 (1H, d), 6.77 (1H, s), 5.30 (1H, br s), 4.31 (2H, m), 4.26 (2H,m), 4.07 (3H, s), 3.66 (2H, s), 3.55 (2H, m), 2.94 (2H, m), 2.73 (2H,m), 2.49 (2H, m), 2.28 (2H, m). MS (ES) m/z 513 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound (58 mg).

Example 92(4[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)methanoldihydrochloride (a)1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-({[(phenylmethyl)oxy]carbonyl}amino)-4-piperidinecarboxylicacid

A solution of 4-amino-1-{[(1,1-dimethylethyl)oxy]carbonyl}-4piperidinecarboxylic acid (10 g, 43.5 mmol) in water (400 mL),dimethoxyethane (50 mL) and 2% aqueous sodium hydroxide solution (50 mL)was treated at 0° C. with a solution ofN-(benzyloxycarbonyloxy)succinimide (16 g, 65 mmol) in dimethoxyethane(50 mL). The mixture was stirred at room temperature overnight,filtered, concentrated, and extracted with ether. The aqueous phase(pH10) was taken to pH4 with aqueous HCl and extracted with ethylacetate. Drying and evaporation afforded a solid which was trituratedwith ether, filtered and dried in vacuo (7.3 g, 44%). MS (ES) m/z 379(M+H)⁺.

(b) 1-(1,1-dimethylethyl) 4-methyl4-({[(phenylmethyl)oxy]carbonyl}amino)-1,4-piperidinedicarboxylate

A mixture of acid (a) (70.3 g, 19.3 mmol), methyl iodide (1.2 mL) andpotassium carbonate (5.3 g) in acetone (70 mL) was stirred for 3 daysthen filtered and evaporated. The residue was partitioned between ethylacetate and water. The organic phase was dried and evaporated affordingan oil (7 g, 92%). MS (ES) m/z 393 (M+H)⁺.

(c) methyl4-({[(phenylmethyl)oxy]carbonyl}amino)-4-piperidinecarboxylate

A solution of carbamate (b) (7 g, 17.8 mmol) in dichloromethane (35 mL)was treated with TFA (35 mL). After 1.5 hours the mixture wasevaporated. The residue was partitioned between 10% methanol indichloromethane and saturated aqueous sodium bicarbonate solution. Theorganic extract was dried and evaporated to give an oil (5.6 g, 100%).MS (ES) mm/z 293 (M+H)⁺.

(d) Methyl1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-({[(phenylmethyl)oxy]carbonyl}amino)-4-piperidinecarboxylate

A mixture of vinyl-quinoline (31e) and piperidine (c) was treated as inexample (52h) to afford the desired product in 87% yield. MS (ES) m/z496 (M+H)⁺.

(e) Methyl4-amino-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinecarboxylate

A solution of protected amine (d) in ethanol was hydrogenated withpalladium on charcoal to afford the product as an oil in a 90% yield. MS(ES) m/z 362 (M+H)⁺.

(f) methyl4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinecarboxylate

The amine (e) and aldehyde (2c) were treated as in example (2d) (exceptthat 1.4 equivalent of aldehyde and 11.8 equivalent of sodiumtriacetoxyborohydride were needed) to afford the desired product in 62%yield.

MS (+ve ion electrospray) m/z 511 (MH+).

(g) Title Compound

A solution of ester (f) (68 mg, 0.13 mmol) in anhydrous tetrahydrofuran(5 mL) was cooled in an ice-bath for 30 minutes. A 1M solution oflithium aluminium hydride (0.14 mL, 0.14 mmol) in diethyl ether wasadded dropwise and the mixture was stirred for 1 hour at 0° C. thenallowed to warm to room temperature. A few drops of diluted sodiumhydroxide were added, the mixture was filtered through Kieselguhr andwashed through with ethyl acetate. The filtrate was evaporated undervacuum. The residue was chromatographed eluting with 5-10% methnaol indichloromethane to afford the desired product as an oil (44 mg, 69%).

1H NMR δH (CDCl₃) 8.59 (1H, s), 8.09 (1H, s), 7.99 (1H, d), 7.31 (1H,dd), 7.23 (1H, d), 6.76 (1H, s), 4.32 (2H, m), 4.26 (2H, m), 3.95 (3H,s), 3.71 (2H, s), 3.40 (2H, s), 3.27 (2H, t), 2.79-2.53 (6H, m),1.79-1.58 (4H, m). MS (ES) m/z 483 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thedihydrochloride salt of the title compound.

Example 93N-[1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-(hydroxymethyl)-4-piperidinyl]-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamidehydrochloride (a) 1,1-dimethylethyl4-amino-4-(hydroxymethyl)-1-piperidinecarboxylate

A solution of ester (87a) (1 g, 3.88 mmol) in anhydrous tetrahydrofuran(10 mL) was cooled in an ice-bath. A 1M solution of lithium aluminiumhydride in tetrahydrofuran (7.76 mL, 7.76 mmol) was added dropwise andthe reaction mixture was stirred at 0° C. for 1.5 hours. Several dropsof diluted sodium hydroxide were added cautiously. The mixture wasfiltered through Kieselguhr, washed through with ethyl acetate andevaporated under vacuum. The residue was chromatographed on silica geleluting with 5-20% methanol in ethyl acetate to afford the product as anoil (0.37 g, 41%). MS (ES) m/z 231 (M+H)⁺.

(b) 1,1-dimethylethyl4-(hydroxymethyl)-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)carbonyl]amino}-1-piperidinecarboxylate

A solution of acid (7b) (0.34 g, 1.61 mmol) in DMF (10 mL) was treatedwith triethylamine (0.45 mL, 3.3 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.63 g, 1.65 mmol). The mixture was stirred for 45minutes and was added to aminoalcohol (a) (0.37 g, 1.61 mmol). Thereaction mixture was stirred at room temperature for 18 hours andevaporated under vacuum. The residue was slurried with water. Aprecipitate was formed, filtered, washed with water and dried in vacuoto afford the product (0.4 g, 59%).

MS (ES) m/z 423 (M+H)⁺.

(c)N-[4-(hydroxymethyl)-4-piperidinyl]-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide

A solution of protected amine (b) (0.4 g, 0.95 mmol) in dichloromethane(10 mL) was treated with trifluoroacetic acid (10 mL). The reactionmixture was stirred at room temperature for 1.5 hours and evaporatedunder vacuum. The residue was dissolved in a minimum volume of water andbasified by addition of sodium bicarbonate. The aqueous layer wasextracted several times with 10% methanol in dichloromethane (withaddition of sodium chloride). As the extraction was incomplete, theaqueous layer was acidified with a 2M solution of HCl and evaporated todryness. The residue was extracted with 10% methanol in dichloromethaneseveral more times. The combined organic extracts were dried overmagnesium sulfate, filtered and evaporated to afford the product as anoil (0.3 g, 98%). MS (ES) m/z 323 (M+H)⁺.

(d) Title Compound

A mixture of vinyl-naphthyridine (53h) and piperidine (c) was treated asin example (52h) to afford the desired product in 45% yield.

1H NMR δH (CDCl₃) 8.61 (1H, s), 8.25 (1H, br s), 8.18 (1H, d), 7.84 (1H,d), 7.79 (1H, d), 7.07 (1H, d), 4.06 (3H, s), 3.81 (2H, s), 3.54 (2H,s), 3.41 (2H, m), 2.84 (2H, m), 2.78 (2H, m), 2.43 (2H, t), 2.10 (2H, brd), 1.84 (2H, m). MS (ES) m/z 527 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound.

Example 94N-(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxamidehydrochloride

Acid (see Example 65) and amine (31g) were treated as in example (93b)to afford the free base of the title compound in 81% yield.

1H NMR δH (d6-DMSO) 8.78 (1H, s), 8.16 (1H, brs), 8.02 (1H, d), 7.62(1H, d), 7.48 (2H, 2×d), 7.39 (1H, d), 4.76 (2H, s), 4.01 (3H, s), 3.78(1H, br), 3.57-3.17 (6H, m), 2.13 (2H, br m), 1.85 (2H, br m). MS (ES)m/z 480 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound.

Example 95N-(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)₃-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamidehydrochloride

Acid (7b) and amine (31g) were treated as in example (93b) to afford thefree base of the title compound in 66% yield.

1H NMR δH (CDCl₃/CD₃OD) 8.59 (1H, s), 8.01 (1H, d), 7.83 (1H, d), 7.78(1H, d), 7.74 (1H, br), 7.35 (1H, dd), 7.25 (1H, d), 4.04 (1H, m), 3.99(3H, s), 3.54 (2H, s), 3.31 (2H, m), 3.12 (2H, m), 2.74 (2H, m), 2.40(2H, t), 2.09 (2H, br d). MS (ES) m/z 496 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound.

Example 967-{[((3R,4S)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-onedihydrochloride Enantiomer 1

Amine (34b) and aldehyde (see Example 48) were treated as in example(47m) to afford the free base of the title compound in 56% yield.

1H NMR δH (CDCl₃) 8.90 (1H, bs), 8.14 (1H, d), 8.01 (1H, d), 7.32 (1H,dd), 7.22 (1H, d), 7.17 (1H, d), 3.96 (3H, s), 3.90 (1H, s), 3.81 (2H,q), 3.57 (2H, s), 3.21 (2H, t), 3.11 (1H, d), 2.95 (1H, d), 2.73 (2H,m), 2.52 (1H, m), 2.30 (1H, d), 2.18 (1H, m), 1.77 (2H, m), 1.66 (2H,m). MS (ES) m/z 498 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound.

Example 976-{[((3R,4S)-1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer 1 (a) 8-fluoro-6-(methoxy)-4(1H)-quinolinone

A mixture of 2-fluoro-4-methoxy-phenylamine (3.80 g; 26.7 mmol) andmethyl propiolate (2.4 mL, 0.267 mol) in methanol (100 mL) was stirredfor 72 hours at room temperature, then heated at 50° C. for 24 hours. Itwas evaporated and the product purified by chromatography on silica gel(dichloromethane) to give a solid (1.66 g), a portion of which wasrecrystallised from dichloromethane-hexane.

This solid (0.96 g) in warm Dowtherm A (5 mL) was added over 3 minutesto refluxing Dowtherm A (15 mL), and after a further 20 minutes atreflux the mixture was cooled and poured into ether. The precipate wasfiltered to give a solid (0.50 g, 61%). MS (ES) m/z 194 (M+H)⁺.

(b) 3-chloro-8-fluoro-6-(methoxy)-4(1H)-quinolinone

Quinolone (a) (14.8 g, 76.7 mmol) in acetic acid (150 mL) was treatedwith N-chlorosuccinimide (11.3 g, 84.4 mmol) and the mixture was heatedat 40° C. for 18 hours, cooled, the precipitate was filtered and driedunder vacuum to afford the product as a solid (8.5 g, 49%). MS (ES) m/z227/229 (M+H)⁺.

(c) 3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl trifluoromethanesulfonate

A suspension of 60% sodium hydride in oil (2.24 g, 56.04 mmol) waswashed with hexane, the hexane solution decanted, and dry DMF (100 mL)added followed by quinolone (b) (8.5 g, 37.36 mmol). The mixture wasstirred at room temperature for 15 minutes, cooled in ice andN-phenyltrifluoromethanesulphonimide (14.7 g, 41.09 mmol) added and themixture was allowed to stir at room temperature overnight. It wasevaporated under vacuum and the residue was chromatographed on silicagel eluting with hexane/dichloromethane to afford the product as a solid(13.9 g, 100%). MS (+ve ion electrospray) m/z 357/359 (MH+).

(d) 3-chloro-4-ethenyl-8-fluoro-6-(methoxy)quinoline

Triflate (c) was treated as in example (23f) to afford the product in72% yield. MS (+ve ion electrospray) m/z 239/241 (MH+).

(e) 1,1-dimethylethyl((3R,4S)-1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)carbamate

Vinyl-quinoline (d) and piperidine (5c, Enantiomer 1) were treated as inExample (52h) to afford the adduct in 55% yield. MS (+ve ionelectrospray) m/z 454/456 (MH+).

(f)(3R,4S)-4-amino-1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-piperidinol

Carbamate (e) was treated as in example (66b) to afford the amine in 86%yield.

MS (+ve ion electrospray) m/z 354/356 (MH+).

(g) Title Compound

Amine (f) and aldehyde (7d) were treated as in example (47m) to affordfree base of the title compound in 60% yield.

1H NMR δH (CDCl₃) 9.20 (1H, bs), 8.66 (1H, s), 7.57 (1H, d), 7.09 (1H,dd), 7.04 (1H, d), 6.98 (1H, d), 3.94 (3H, s), 3.93 (1H, s), 3.89 (2H,q), 3.44 (2H, s), 3.55 (2H, m), 3.16 (1H, d), 3.00 (1H, d), 2.67 (3H,m), 2.37 (1H, d), 2.26 (1H, m), 1.79 (2H, m).

MS (+ve ion electrospray) m/z 533/535 (MH+).

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound.

The following example was prepared by analogous method to Example 97using the aldehydes shown:

Example 98 (3R,4S)-1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinol dihydrochloride

Aldehyde is 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7- carbaldehyde as inexample (2c)

Example 992-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}-1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethanolDihydrochloride Hydrate Enantiomer 1 (a)1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]-1,2-ethanediol

To a solution of AD-mixβ (50 g) in tert-butanol/water (200 mL/200 mL),cooled in an ice-bath for 30 minutes, vinyl-naphthyridine (53h) (8 g,39.2 mmol) was added and the reaction mixture was stirred at roomtemperature for 48 hours. Sodium sulfite (75 g) was added and themixture was stirred for a further 30 minutes. It was extracted withdiethyl ether then several times with 10% methanol in chloroform. Theorganic extract was evaporated under vacuum to afford the desiredproduct as an oil (8.93 g, 96%). MS (+ve ion electrospray) m/z 239(MH+).

enantiomeric excess=44%, as determined by chiral analytical hplc

(b) 2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]-2-hydroxyethyl4-methylbenzenesulfonate

To a solution of diol (a) (16.5 g) in dichloromethane (200 mL),triethylamine (10 mL) and dibutyltin oxide (350 mg) was added tosylchloride (13.2 g). After 3 hours, the mixture was diluted withwater/sodium bicarbonate and extracted several times with chloroform.The combined organic extracts were dried over magnesium sulfate andevaporated under vacuum. The residue was chromatographed on silica geleluting with 20-30% ethyl acetate in chloroform to afford the desiredproduct (20.3 g, 75%). MS (+ve ion electrospray) m/z 393 (MH+).

(c) 7-fluoro-2-(methoxy)-8-(2-oxiranyl)-1,5-naphthyridine

To a suspension of tosylate (b) (10.5 g, 26.7 mmol) in anhydrousmethanol (160 mL), cooled in an ice-bath, potassium carbonate (7.03 g,50.9 mmol) was added. After 15 minutes with cooling, the mixture wasstirred at room temperature for a further 1.75 hours. It was thendiluted with water, extracted several times with dichloromethane, driedover magnesium sulfate and evaporated under vacuum. The residue waschromatographed on silica gel eluting with dichloromethane, chloroformthen 20% ethyl acetate in chloroform to afford the product as an oil(5.55 g, 94%). MS (+ve ion electrospray) m/z 221 (MH+).

(d) phenylmethyl4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinecarboxylate

Piperidin-4-yl-carbamic acid tert-butyl ester (21 g, 0.10 mol) was addedto a well stirred mixture of ethyl acetate (640 mL) and saturated sodiumbicarbonate (533 mL). After 5 minutes, phenylmethyl chloridocarbonatewas added dropwise over 10 minutes. The mixture was stirred at roomtemperature for 18 hours. The phases were separated. The organic layerwas washed with diluted HCl and bicarbonate, dried over magnesiumsulfate and evaporated under vacuum to afford the product as a whitesolid (29.3 g, 83%). MS (+ve ion electrospray) m/z 336 (MH+).

(e) phenylmethyl 4-amino-1-piperidinecarboxylate

Carbamate (d) (19 g, 57 mmol) was dissolved in dichloromethane (200 mL)and treated with trifluoroacetic acid (120 mL). After 1 hour the mixturewas evaporated and the residue partitioned between ethyl acetate andsaturated aqueous sodium bicarbonate solution. The ethyl acetate extractwas dried and evaporated affording an oil in quantitative yield (13.3g).

MS (+ve ion electrospray) m/z 236 (MH+).

(f) phenylmethyl4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinecarboxylate

Amine (e) (5.5 g) and aldehyde (2c) (3.3 g) were dissolved indichloromethane/methanol (100 mL/5 mL) and treated with sodiumtriacetoxyborohydride (6.5 g, ˜1.5 equivalents). After 16 hours themixture was partitioned between dichloromethane and saturated aqueoussodium bicarbonate. The organic extract was dried and evaporated to givean oil. Chromatography on silica eluting with 0-15% methanol indichloromethane afforded an oil (6.4 g, 83%).

MS (+ve ion electrospray) m/z 384 (MH+).

(g) phenylmethyl4-((2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl){[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinecarboxylate

A solution of amine (f) (14.4 g, 37 mmol) in anhydrous methanol (150 mL)was treated with sodium bicarbonate (9.02 g, 107 mmol) andbis(1,1-dimethylethyl) dicarbonate (15.6 g, 71 mmol). The mixture wasstirred at room temperature for 18 hours. The mixture was filtered,evaporated under vacuum and the residue was chromatographed on silicagel eluting with 0-50% ethyl acetate in hexane to afford the product asan oil (13.5 g, 100%).

MS (+ve ion electrospray) m/z 484 (MH+).

(h) 1,1-dimethylethyl(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)₄-piperidinylcarbamate

A solution of piperidine (g) (13.5 g, 27.9 mmol) in ethanol (200 mL) washydrogenated with 10% palladium on charcoal at room temperature for 18hours. The reaction mixture was filtered through Kieselguhr andevaporated under vacuum to afford the product as an oil (9.7 g, 99%).

MS (+ve ion electrospray) m/z 349 (MH+).

(i) 1,1-dimethylethyl(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)(1-(2-(3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]-2-hydroxyethyl)-4-piperidinyl)carbamate

A mixture of epoxide (c) (1.83 g, 8.3 mmol), amine (h) (3.2 g, 9.1 mmol)and lithium perchlorate (0.88 g, 8.3 mmol) in acetonitrile (50 mL) wasstirred at room temperature for 48 hours. The mixture was diluted withwater/sodium carbonate and extracted several times with dichloromethane.The extracts were dried over magnesium sulfate and evaporated undervacuum. The residue was chromatographed on silica gel eluting with 0-3%methanol in dichloromethane to afford the product as an oil (3.72 g,78%).

MS (+ve ion electrospray) m/z 570 (MH+).

(j) Title Compound

Carbamate (i) (3.72 g, 6.5 mmol) was dissolved in dichloromethane (70mL) and treated with trifluoroacetic acid (10 mL). After 3 hours themixture was evaporated and the residue partitioned between 10%methanol/dichloromethane and aqueous sodium carbonate solution. Theaqueous phase was further extracted with 10% methanol/dichloromethane toafford a white foam (2.85 g, 93%).

This material was subjected to preparative hplc using a Kromasil C18 (4inch column) to remove unwanted regioisomers then further purified byChiralpak AD (3 inch column) to separate the enantiomers. This processafforded the free base of the title compound as the major, first eluted,isomer, as a white foam, (820 mg) which had >99% chemical andenantiomeric purity, [α]_(D) (25° C.)=−6.1 degrees (c=1%, methanol).

1H NMR δH (400 mHz, CD₃OD) 8.68 (1H, s), 8.25 (1H, d), 8.01 (1H, s),7.21 (1H, d), 6.97 (1H, s), 6.03 (1H, m), 4.25-4.45 (4H, m), 4.11 (3H,s), 3.78 (2H, s), 2.90-3.20 (4H, m), 2.85 (1H, m), 2.50 (1H, m), 2.25(2H, m), 1.89 (2H, m), 1.30-1.50 (2H, m)

MS (ES) m/z 470 (M+H)⁺.

This material was dissolved in ethanol and treated with 2.2 equivalentsof 6M aqueous HCl. Crystallisation was aided by the addition ofisopropanol affording after filtration and drying the title compound asa white solid, m.p. 198-200° C. In general, either enantiomer wasobtained with moderate to good selectivity using chiral agents (AD-mixαor AD-mixβ) for the dihydroxylation step. Purification to >99% opticalpurity was accomplished by chiral preparative hplc in a manner analogousto that of Example 99.

Example 1002-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}-1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethanolDihydrochloride Hydrate Enantiomer 2

This Example was prepared exactly as described for Example 99, but usingAD-mix a in the dihydroxylation step (98a). The compound was eluted fromthe HPLC Chiralpak AD column as the major, second eluting, isomer.

[α]_(D) (25° C.)=+6.3 degrees (c=1%, methanol).

It was converted to the hydrochloride by the method of Example 99.

Example 101 racemic,cis4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinyl)methanoldihydrochloride (a)4-Benzylamino-1-tert-butoxycarbonyl-3-ethoxycarbonyl-1,2,5,6-tetrahydropyridine

A solution of 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperidin-4-one(prepared from 3-ethoxycarbonylpiperidin-4-one anddi-tert-butyl-dicarbonate in dichloromethane and triethylamine) (25g)and benzylamine (10.85 g) in toluene was heated under reflux in a Deanand Stark apparatus for 18 hours and then evaporated to dryness to givean oil.

(b)racemic,cis-4-Benzylamino-1-tert-butoxycarbonyl-3-ethoxycarbonylpiperidine

The enamine (a) (25g) in ethanol (300 ml) was hydrogenated over platinumoxide (1.5 g) for 4 days, filtered, and evaporated to dryness. It waschromatographed on silica gel (ethyl acetate-hexane) to afford the titlecompound as an oil.

MS (+ve ion electrospray) m/z 363 (MH+).

(c) racemic,cis-4-Amino-1-tert-butoxycarbonyl-3-ethoxycarbonylpiperidine

The amine (b) (4g) in ethanol (80 ml) containing acetic acid (0.73 g)was hydrogenated at 50 psi (Parr reaction vessel) over 10%palladium-carbon (1g) for 18 hours, filtered and evaporated to drynessto afford the acetate salt of the title compound as a white solid (3g).

MS (+ve ion electrospray) m/z 273 (MH+).

(d) racemic,cis 1-(1,1-dimethylethyl)3-ethyl-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1,3-piperidinedicarboxylate

To the acetate salt (c) (2.2 g, 8 mmol) in chloroform, sodium carbonatewas added. The mixture was extracted several times with 10% ethanol inchloroform. The organic extracts were dried over sodium sulfate,filtered and evaporated under vacuum to afford an oil.

The oil (2.2 g) in ethanol/chloroform (5 mL/5 mL) was heated withaldehyde (2c) (1.33 g, 8 mmol) at 70° C. for 3 hours. The reactionmixture was cooled and sodium triacetoxyborohydride (5.14 gm 24 mmol)was added. The reaction mixture was stirred at room temperature for 18hours. It was filtered. Chloroform and sodium carbonate were added. Thesolution was extracted several times with chloroform. The combinedorganic extracts were dried over sodium sulfate and evaporated undervacuum. The residue was chromatographed on silica gel eluting withdichloromethane then 2% methanol in dichloromethane to afford theproduct as an oil (2 g, 59%) MS (+ve ion electrospray) m/z 422 (MH+).

(e) racemic,cisethyl-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinecarboxylate

Protected piperidine (d) was treated as in example (66b) to afford theproduct as an oil in a quantitative yield. MS (+ve ion electrospray) m/z322 (MH+).

(f) racemic,cisethyl-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinecarboxylate

A mixture of vinyl-naphthyridine (53h) and piperidine (e) was treated asin example (52h) to afford the product in a 26% yield. MS (+ve ionelectrospray) m/z 526 (MH+).

(g) Title Compound

A solution of ester (f) (0.1 g, 0.19 mmol) in anhydrous diethylether/tetrahydrofuran (10 mL/0.4 mL) was cooled to −5° C. in anethanol-ice bath. A 1M solution of lithium aluminium hydride (0.4 mL,0.4 mmol) in diethyl ether was added and the reaction mixture wasstirred for 1.5 hour at −5° C. The reaction mixture was evaporated undervacuum. Chloroform and an aqueous solution of sodium carbonate wereadded. The aqueous was extracted several times with chloroform, driedover sodium sulfate and evaporated. The residue was chromatographed andsilica gel, eluting with 2-10% methanol in dichloromethane to afford thefree base of the title compound as an oil (45 mg).

1H NMR δH (400 mHz, CDCl₃) 8.60 (1H, s), 8.18 (1H, d), 8.09 (1H, s),7.07 (1H, d), 6.80 (1H, s), 4.25-4.40 (4H, m), 4.10 (3H, s), 3.98 (1H,m), 3.70-3.95 (3H, m), 3.40 (2H, m), 2.88 (2H, m), 2.70 (2H, m), 2.40(1H, br.d), 2.28 (1H, br. t), 2.05 (1H, m), 1.92 (1H, m), 1.70 (1H, m).

MS (ES) m/z 484 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound (55 mg).

Example 102racemic,cis-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinecarboxylicacid dihydrochloride

Ester (101f) (0.27 g, 0.5 mmol) was treated with a 2M solution of HCl.The reaction mixture was heated at 90° C. for 5 hours. It was evaporatedunder vacuum and taken to pH 5-6 by addition of a solution of sodiumbicarbonate. The aqueous was extracted several times with 5% methanol inchloroform, dried over sodium sulfate and evaporated under vacuum. Theresidue was chromatographed on a silica gel column eluting with 2-30%methanol in chloroform to afford the free base of the title compound asan oil (30 mg)

1H NMR δH (400 mHz, CD₃OD) 8.60 (1H, s), 8.19 (1H, d), 8.08 (1H, s),7.15 (1H, d), 7.00 (1H, s), 4.25-4.42 (4H, m), 4.18 (2H, m), 4.10 (3H,s), 3.40-3.70 (3H, m), 3.30 (m (under MeOD)), 3.13 (1H, m), 2.85 (3H,m), 2.50 (2H, m), 1.90-2.18 (2H, m). MS (ES) m/z 498 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound (26 mg).

Example 103racemic,cis-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinecarboxamidedihydrochloride (a)1,1-dimethylethyl-3-(aminocarbonyl)-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinecarboxylate

A solution ester (101d) (1 g, 2.3 mmol) in anhydrous methanol (20 mL)and sodium cyanide (50 mg) was treated with liquid ammonia (30 mL). Thereaction mixture was sealed in a 500 mL Berghoff bomb and heated at 55°C. for 72 hours. The mixture was evaporated to dryness andchromatographed on silica gel eluting with dichloromethane and 1-10%methanol in dichloromethane to afford the product as an oil (40 mg,43%).

MS (ES) m/z 393 (M+H)⁺.

(b)(3R,4S)-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinecarboxamide

Protected piperidine (a) was treated as in example (66b) to afford theproduct as an oil in a quantitative yield.

MS (+ve ion electrospray) m/z 392 (MH+).

(c) Title Compound

A mixture of vinyl-naphthyridine (53h) and piperidine (b) was treated asin example (52h) to afford the free base of the title compound in 88%yield.

MS (+ve ion electrospray) m/z 526 (MH+).

1H NMR δH (400 mHz, CDCl₃) 8.60 (1H, s), 8.19 (1H, m), 8.17 (1H, d),8.09 (1H, s), 7.10 (1H, d), 6.86 (1H, s), 5.10 (1H, m), 4.25-4.42 (4H,m), 4.09 (3H, s), 3.98 (1H, d), 3.78 (1H, d), 3.48 (1H, m), 3.34 (1H,m), 3.21 (2H, br.d), 2.80 (4H, m), 2.30 (1H, br.d), 2.17 (1H, br.t),1.60-1.90 (4H, m).

MS (ES) m/z 496 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound (35 mg).

Example 1041-{2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-N-[(6-oxido-2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-yl)methyl]-4-piperidinaminedihydrochloride (a)(6-oxido-2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-yl)methanol

A solution of alcohol (2b) (0.5 g, 2.9 mmol) in chloroform (30 mL) wastreated with m-chloroperbenzoic acid (2 g). The mixture was stirred atroom temperature for 18 hours. The desired product precipitated out as asolid and was isloated by filtration. Sodium carbonate and water wereadded to the filtrate whereupon further solid precipitated out. This wasalso filtered off, dried and combined with the first solid (in total,0.25 g, 46%). MS (+ve ion electrospray) m/z 184(MH+).

(b) 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde 6-oxide

N-oxide (a) (0.25 g, 1.3 mmol) in chloroform (120 mL) was warmed andsonicated. Manganese dioxide (0.5 g) as added and the mixture wasstirred at room temperature for 18 hours. The reaction mixture wasfiltered through celite and evaporated under vacuum to afford theproduct as a yellow solid (100 mg, 40%).

MS (+ve ion electrospray) m/z 182(MH+).

(c) Title Compound

Amine (3c) (45 mg, 0.14 mmol) and aldehyde (b) were treated as inexample (53j) to afford the free base of the title compound as an oil ina 51% yield.

1H NMR δH (400 mHz, CDCl₃) 8.68 (1H, s), 8.16 (1H, d), 7.99 (1H, s),7.10 (1H, d), 6.98 (1H, s), 4.25-4.42 (4H, m), 4.09 (3H, s), 3.97 (2H,s), 3.57 (2H, m), 3.08 (2H, br.d), 2.70 (2H, m), 2.50 (1H, m), 2.20 (4H,m), 1.95 (1H, br.d), 1.50 (1H, m). MS (ES) m/z 486/488 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound (40 mg).

Example 1056-{[(1-{2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]-3-hydroxypropyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride (a) methyl 2-(tributylstannanyl)propenoate

To a solution of methyl propiolate (2 mL, 22.48 mmol) andbis(triphenylphosphine)palladium(II) chloride (316 mg, 0.45 mmol) intetrahydrofuran, tri-N-butyltin hydride was added dropwise and thereaction mixture was stirred at room temperature for 30 minutes. It wasthen evaporated under vacuum. The residue was chromatographed on silicagel eluting with petroleum ether to afford the product as a colourlessoil in a quantitative yield.

MS (ES) m/z 375 (M+H)⁺.

(b) methyl 2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]-2-propenoate

To a solution of naphthyridine-triflate (1b, 4.88 mmol) in DMF (30 mL)was added stannane (a) (2.75 g, 7.33 mmol),tetrakis(triphenylphosphine)palladium(0) (564 mg, 0.49 mmol), lithiumchloride (207 mg, 4.88 mmol) and cupper iodide (697 mg, 3.66 mmol). Thereaction mixture was stirred at room temperature for 24 hours, then at70° C. for a further 2 hours and at 100° C. for an other 18 hours. Thereaction mixture was filtered and worked-up to afford the desiredproduct in a 52% yield.

MS (ES) m/z 278/280 (M+H)⁺.

(c) methyl2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]-3-[4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]propanoate

Propenoate (b) and piperidin-4-yl-carbamic acid tert-butyl ester weretreated as in example (52h) to afford the adduct in 90% yield. MS (ES)m/z 477/479 (M+H)⁺.

(d) 1,1-dimethylethyl(1-{2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]-3-hydroxypropyl}-4-piperidinyl)carbamate

Ester (c) was reduced with lithium aluminium hydride as in example (92g)to afford the alcohol in 16% yield.

MS (ES) m/z 449/451 (M+H)⁺.

(e)3-(4-amino-1-piperidinyl)-2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]-1-propanol

Carbamate (d) was dissolved in dichloromethane and treated with excessHCl in dioxan. After stirring for 2 hours, the reaction mixture wasevaporated under vacuum. The crude HCl salt was neutralised andextracted by the workup procedure of Example (66b) affording the freeamine in quantitative yield.

MS (ES) m/z 349/351 (M+H)⁺.

(f) Title Compound

Piperidine (e) and aldehyde (7d) were treated as in Example (53j) toafford the free base of the title compound in 60% yield.

¹H NMR δH (d4-MeOH) 8.66 (1H, s), 8.18 (1H, d), 7.64 (1H, d), 7.18 (1H,d), 4.27 (1H, m), 4.10 (1H, m), 4.06 (2H, s), 3.77(2H, s), 3.48 (2H, s),3.35 (4H, m), 3.20-3.15 (1H, m), 3.06 (1H, d), 2.91 (1H, d), 2.47 (1H,m), 2.06 (2H, t), 1.90-1.83 (2H, m), 1.36-1.27 (2H, m). MS (ES) m/z531/533 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound.

Example 1066-[({1-[2-(3,6-difluoro-4-quinolinyl)ethyl]-4-piperidinyl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride (a) 4-ethenyl-3,6-difluoroquinoline

4-Fluoroaniline was converted through the same series of reactions asoutlined in Example (47 c-j) to afford the desired vinyl-quinoline as anoil. MS (ES) m/z 192 (M+H)⁺.

(b) 1,1-dimethylethyl{1-[2-(3,6-difluoro-4-quinolinyl)ethyl]-4-piperidinyl}carbamate

Vinyl quinoline (a) (0.1 g, 0.5 mmol) and piperidin-4-yl-carbamic acidtert-butyl ester (0.1 g, 0.5 mmol) in DMF (0.2 mL/mmol) were treated asin Example (47k) to afford the product as a solid (0.17 g, 86%). MS (ES)m/z 391 (M+H)⁺.

(c) 1-[2-(3,6-difluoro-4-quinolinyl)ethyl]-4-piperidinamine

Carbamate (b) was treated with trifluoroacetic acid as in Example (471)to afford the product as a solid (0.13 g, 97%). MS (ES) m/z 291 (M+H)⁺.

(d) Title Compound

Amine (c) and aldehyde (7d) were treated as in example (47m) to affordthe free base of the title compound as a solid (0.13 g, 65%).

¹H NMR δH (d4-MeOH) 8.71 (s, 1H), 8.1 (dd, 1H), 7.8 (dd, 1H), 7.75 (d,1H), 7.53-7.59 (m, 1H), 7.08 (s, 1H), 4.13 (s, 2H), 3.53 (s, 2H), 3.36(m, 2H), 3.29-3.35 (m, 3H), 3.17-3.22 (m, 2H), 2.91-3.09 (m, 1H),2.75-2.78 (m, 2H), 2.23-2.33 (m, 2H), 2.11-2.15 (m, 2H), 1.61-1.71 (m,2H). MS (ES) m/z 469 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound (155 mg).

The following examples were prepared by analogous method to Example 106:

Example 107 1-[2-(3,6-difluoro-4-quinolinyl)ethyl]-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4- piperidinaminehydrochloride dihydrochloride

Aldehyde is 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7- carbaldehyde as inexample (2c) 108 6-[({1-[2-(3,6-difluoro-4-quinolinyl)ethyl]-4-piperidinyl}amino)methyl]-2H-pyrido[3,2- b][1,4]oxazin-3(4H)-onedihydrochloride

Aldehyde is 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde as in example (1l)

Example 1096-{[(1-{2-[3-chloro-6-fluoro-5-(methoxy)-4-quinolinyl]-1-methylethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride

Amine (22l) and aldehyde (1l) were treated as in example (22m) to affordthe free base of the title compound as a solid in 65% yield.

¹H NMR δH (d4-MeOH) 8.72 (s, 1H), 7.81 (dd, 1H), 7.65 (dd, 1H), 7.34 (d,1H), 7.03 (d, 1H), 4.76 (s, 2H), 4.12 (s, 3H), 4.10-4.12 (m, 1H),3.70-4.12 (m, 2H), 3.35 (m, 3H), 3.30-3.31 (m, 2H) 3.20-3.25 (m, 2H),3.00 (m, 1H), 2.73-2.80 (m, 2H), 2.32-2.42 (m, 2H), 2.12-2.17 (m, 2H),1.68-1.74 (m, 2H). MS (ES) m/z 499 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound (34 mg).

The following example was prepared by analogous methods to Example 109:

Example 110 1-{2-[3-chloro-6-fluoro-5-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4- piperidinaminedihydrochloride

Aldehyde is 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7- carbaldehyde as inexample (2c)

Example 1111-[2-(6-chloro-3-fluoro-4-quinolinyl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-N-methyl-4-piperidinecarboxamidedihydrochloride (a) 6-chloro-4-ethenyl-3-fluoroquinoline

4-Chloroaniline converted through the same series of reactions asoutlined in Example (47 a-j) to afford the desired vinyl-quinoline as anoil.

MS (ES) m/z 208 (M+H)⁺.

(b) Title Compound

Vinyl-quinoline (a) and piperidine (87e) were treated as in Example(52h) to afford the free base of the title compound as an oil.

1H NMR δH (CDCl₃) 8.72 (1H, s), 8.13 (1H, s), 8.02 (1H, d), 7.98 (1H,d), 7.87 (1H, m), 7.59 (1H, dd), 6.74 (1H, s), 4.31 (2H, m), 4.27 (2H,m), 3.59 (2H, s), 3.23 (2H, br t), 2.89 (2H, m), 2.78 (3H, d), 2.66 (2H,m), 2.42 (2H, t), 2.28 (2H, td), 1.69 (2H, br d).

MS (ES) m/z 515 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound.

Example 1122-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}-1-[3-fluoro-6-(methoxy)-4-quinolinyl]ethanoldihydrochloride Enantiomer 2

Vinyl-quinoline (31e) was taken through the sequence outlined in Example(99), using AD-mixα as a chiral agent for the dihydroxylation step.Final purification was by chiral preparative hplc, again in a manneranalogous to that described in Example (100), affording the free base ofthe title compound as a foam, as the major, second eluting enantiomer.

1H NMR δH (400 mHz, CDCl₃) 8.56 (1H, s), 8.10 (1H, s), 7.95 (1H, d),7.92 (1H, d), 7.29 (1H, dd), 6.83 (1H, s), 5.58 (1H, dd), 4.25-4.35 (4H,m), 3.93 (3H, s), 3.81 (2H, s), 3.18 (1H, m), 3.03 (1H, m), 2.90 (1H,m), 2.60 (2H, m), 2.49 (1H, br.t), 2.18 (1H, br.t), 1.90 (2H, m), 1.80(2H, m), 1.40-1.65 (2H, m)

MS (ES) m/z 469 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid (530 mg)

Example 1136-{[trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E2 (a) 1,1-dimethylethyl((trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)carbamate,Isomer E2

Vinyl naphthyridine (53h) (1.25 g, 6.1 mmole) was heated to 100° C.together with trans-1,1-dimethylethyl (3-hydroxy-4-piperidinyl)carbamate(prepared by hydrogenation of Example 17f, Isomer E2) (1.32 g, 6.1mmole) in DMF (5 mL). After 24 hours, the mixture was concentrated invacuo and purified on silica (CHCl₃/MeOH with 5% NH₄OH, 9:1) to give theproduct as an oil (1.9 g, 75%).

MS (ES) m/z 421 (M+H)⁺.

(b) Title Compound

To a solution of carbamate (a) (1.9 g, 4.57 mmole) in dichloromethane(100 mL) was added 4M HCl in dioxane (20 mL). After stirring for 3 h,the reaction contents were concentrated under vacuum to give a whitesolid which was used without further purification (98%). MS (ES) m/z 321(M+H)⁺.

To a solution of the above piperidinol hydrochloride salt (ca. 1.0mmole) in ethanol (20 mL) and dichloromethane (20 mL) was added triethylamine (0.56 mL, 4.0 mmole) and aldehyde (7d) (0.19 g, 1.0 mmole). After24 hours at room temperature, sodium borohydride (42 mg, 1.1 mmole) wasadded and the reaction mixture stirred for 5 hours. Silica gel (˜2 g)was added to the mixture and the reaction contents stirred for anadditional 2 hours. The reaction slurry was concentrated to dryness invacuo and loaded onto a silica gel column (eluting with CHCl₃/MeOH with5% NH₄OH, 9:1) to afford the title compound as a white foam.

This material, as a solution in chloroform/methanol, was treated with anexcess of 2M HCl in ether and evaporated to dryness. The solid wastriturated with ether, filtered and dried under vacuum to provide thetitle compound (71%) as a white solid.

¹H NMR of the dihydrochloride salt δH (CD₃OD) 8.67 (1H, s), 8.31 (1H,d), 7.85 (1H, d), 7.32 (1H, d), 7.17 (1H, d), 4.76 (4H, m), 4.51 (2H,m), 4.43 (1H, m), 4.18 (3H, s), 3.93 (2H, m), 3.87 (2H, m), 3.71 (2H,m), 3.15 (1H, m), 2.59 (1H, s), 2.23 (1H, m). MS (+ve ion electrospray)m/z 499 (M+H)⁺.

Example 1146-{[trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E2

This was prepared by the analogous process to Example (113) with theexception that aldehyde (1l) was used in the reductive alkylation step.

¹H NMR (of the dihydrochloride salt) δH (CD₃OD) 8.93 (1H, s), 8.35 (1H,d), 7.58 (1H, d), 7.37 (1H, d), 7.12 (1H, d), 4.73 (3H, m), 4.44 (2H,m), 4.39 (1H, m), 4.21 (3H, s), 3.85 (3H, m), 3.77 (2H, m), 3.71 (2H,m), 3.18 (1H, m), 2.60 (1H, s), 2.22 (1H, m). MS (+ve ion electrospray)m/z 483 (M+H)⁺.

Example 115trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinoldihydrochloride Enantiomer E2

This was prepared by the analogous process to Example (113) with theexception that aldehyde (2c) was used in the reductive alkylation step.

¹H NMR of the dihydrochloride salt δH (CD₃OD) 8.82 (1H, s), 8.48(1H, s),8.31 (1H, d), 7.59 (1H, s), 7.29 (1H, d), 4.65 (4H, m), 4.51 (2H, m),4.40 (1H, m), 4.21 (3H, s), 3.97 (1H, m), 3.89 (1H, m), 3.80 (2H, m),3.63 (4H, m), 3.19 (1H, m), 2.64 (1H, s), 2.30 (1H, m). MS (+ve ionelectrospray) m/z 470 (M+H)⁺.

Example 1166-{[trans-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E2

This was prepared by the analogous process to Example (113) with theexception that vinyl quinoline (31e) was used in place of vinylnaphthyridine (53h).

¹H NMR of the dihydrochloride salt δH (CDCl₃) 8.60 (1H, s), 8.01 (1H,d), 7.57 (1H, d), 7.32 (1H, d), 7.20 (1H, s), 6.94 (1H, d), 4.07 (1H,d), 3.96 (3H, s), 3.87 (1H, d), 3.62 (1H, m), 3.47 (2H, s), 3.25 (3H,m), 3.02 (1H, m), 2.73 (2H, m), 2.49 (1H, m), 2.13 (3H, m), 1.52 (1H,m).

MS (+ve ion electrospray) m/z 498 (M+H)⁺.

The following example was prepared by analogous methods to Examples115/116

Example 117 trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3- piperidinoldihydrochloride

Aldehyde is 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7- carbaldehyde as inexample (2c)

Example 118N-trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamidehydrochloride Enantiomer E2

To a solution oftrans-4-amino-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinolhydrochloride salt Isomer E2) (see Example 113b for the crudepreparation of this intermediate), (0.62 mmole) in DMF (20 mL) was addedhydroxy benzotriazole hydrate (0.92 g, 0.68 mmole),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g,0.68 mmole), diisopropylethyl amine (0.43 mL, 2.48 mmole) and carboxylicacid (7b) (0.13 g, 0.62 mmole). After stirring for 24 hours, thereaction contents were concentrated in vacuo and purified on silica(CHCl₃/MeOH with 5% NH₄OH, 9:1) to afford the title compound as anoff-white solid.

This material, as a solution in chloroform/methanol, was treated with anexcess of 2M HCl in ether and evaporated to dryness. The solid wastriturated with ether, filtered and dried under vacuum to provide thetitle compound (85%) as a white solid.

¹H NMR of the dihydrochloride salt δH (CDCl₃) 8.61 (1H, s), 8.19 (1H,d), 7.79 (2H, m), 7.31 (1H, d), 7.10 (1H, d), 4.50 (1H, m), 4.15 (3H,s), 3.65-3.89 (4H, m), 3.42 (3H, m), 3.09 (2H, s), 2.92 (2H, m), 2.47(1H, m), 2.11 (1H, m).

MS (+ve ion electrospray) m/z 513 (M+H)⁺.

Example 119N-trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-.yl]ethyl}-3-hydroxy-4-piperidinyl)-2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxamidehydrochloride Enantiomer E2 (a)2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxylic acid

Aldehyde (2c) (1.65 g, 10 mmol) was dissolved in water/acetone (150mL/50 mL) the treated with sulfamic acid (1.3 g) and sodium chlorite(1.2 g) at 0° C. The mixture was allowed to warm to room temperatureover 1 hour, then evaporated to dryness. Chromatography on silicaeluting with 10% methanol/dichloromethane afforded the acid (1.6 g). MS(APCl⁻) m/z 180 ([M−H]⁻,

(b) Title Compound

This was prepared using the sampe procedure as for Example (118) exceptusing carboxylic acid (a) to afford the product as a white solid (79%).

¹H NMR of the dihydrochloride salt δH (CD₃OD) 8.81 (1H, s), 8.54 (1H,s), 8.30 (1H, d), 8.13 (1H, s), 7.28 (1H, d), 4.67 (2H, m), 4.56 (2H,m), 4.19 (3H, s), 3.90 (2H, m), 3.81 (4H, m), 3.65 (2H, m), 3.12 (2H,m), 2.31 (1H, m), 2.17 (1H, m).

MS (+ve ion electrospray) m/z 484 (M+H)⁺.

Example 120 racemic,trans-6{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}3-hydroxy-3-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride (a) 5-methyl-1-(phenylmethyl)-1,2,3,6-tetrahydropyridine

3-Methylpyridine (20 g, 0.215 mmol) and benzyl chloride (25 mL, 0.215mmol) were combined at 25° C. and stirred 24 h. The resulting salt waswashed several times with Et₂O and used without further purification.

MS (+ve ion electrospray) m/z 184 (M+H)⁺.

The above salt (27 g, 0.123 mmol) in EtOH (150 mL) was added dropwise toa solution of NaBH₄ (18.6 g, 0.492 mol) in EtOH (423 mL) at 0° C. Theresulting suspension gradually warmed to 25° C. over 12 hours, wasconcentrated and partitioned between water-dichloromethane. The aqueousphase was washed several times with dichloromethane and the combinedorganic fractions were dried (Na₂SO₄), concentrated and chromatographedon silica gel to afford the product as an orange oil (10 g, 43%).

MS (+ve ion electrospray) m/z 188 (M+H)⁺.

(b) 2-(trimethylsilyl)ethyl 5-methyl-3,6-dihydro-1(2h)-pyridinecarboxylate

To a solution of piperidine (a) (8 g, 42.75 mmol) in dry toluene (43 mL)at 25° C. was added dropwise a solution of 2-(trimethylsilyl)ethylchloridocarbonate (55 mL, 51.3 mmol) [freshly prepared by the procedureof Shute and Rich Synthesis 1987, 346.] and the resulting solutionstirred at 80° C. After 12 hours the solution was concentrated andchromatographed on silica gel eluting with 0-5% MeOH in DCM affordingthe product as an orange oil that was used without further purification(10.39, >quant. contaminated with residual benzyl chloride).

MS (+ve ion electrospray) m/z 242 (M+H)⁺.

(c) 2-(trimethylsilyl)ethyl1-methyl-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate

To a solution of piperidine (b) (10 g, 41.4 mmol) in dry dichloromethane(138 mL) at 0° C. was added m-chloroperbenzoic acid (8.58 g, 49.7 mmol)batchwise. After stirring 12 hours at 25° C., the solution waspartitioned between a 1N aqueous solution of sodium hydroxide anddichloromethane and the aqueous phase was back extracted several timeswith dichloromethane. The combined organic fractions were combined,dried (Na₂SO₄), concentrated and chromatographed on silica gel elutingwith 2% methanol in dichloromethane to afford the product as a clear oil(6 g, 56%). MS (+ve ion electrospray) m/z 258 (M+H)⁺.

(d) 2-(trimethylsilyl)ethyl(3S,4S)-4-amino-3-hydroxy-3-methyl-1-piperidinecarboxylate and2-(trimethylsilyl)ethyl(3R,4R)-4-amino-3-hydroxy-3-methyl-1-piperidinecarboxylate

A solution of epoxide (c) (6 g, 23.3 mmol) in NH₄OH (50 mL) was heatedto 90° C. in a sealed tube. After 12 hours, the resulting solution wasconcentrated and used directly without further purification. MS (+ve ionelectrospray) m/z 275 (M+H)⁺.

(e) 2-(trimethylsilyl)ethyl(3S,4S)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-hydroxy-3-methyl-1-piperidinecarboxylateand 2-(trimethylsilyl)ethyl(3R,4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-hydroxy-3-methyl-1-piperidinecarboxylate

To a solution of aminopiperidine (d) (6 g, 21.86 mmol) in dryacetonitrile (109 mL) at 25° C. were added N,N-diisopropylethylamine(5.7 mL, 32.8 mmol) and bis(1,1-dimethylethyl) dicarbonate (7.5 mL, 32.8mmol). After 1 hour the solution was concentrated and chromatographed onsilica gel eluting with 1% MeOH in DCM containing 1% NH₄OH affording theproduct as a white solid (6.7 g, 82%).

MS (+ve ion electrospray) m/z 397 (M+H)⁺.

(f) 1,1-dimethylethyl[(3S,4S)-3-hydroxy-3-methyl-4-piperidinyl]carbamate and1,1-dimethylethyl [(3R,4R)-3-hydroxy-3-methyl-4-piperidinyl]carbamate

To a solution of protected piperidine (e) (1 g, 2.67 mmol) in dryacetonitrile (27 mL) at 25° C. was added tetrabutylammonium fluoride (1Min THF, 3.2 mL, 3.20 mmol). After stirring at 50° C. for 12 hours, thesolution was concentrated and used without further purification. MS (+veion electrospray) m/z 231 (M+H)⁺.

(g) Rac-1,1-dimethylethyl(3-hydroxy-3-methyl-1-{2-[6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)carbamate

A solution of (racemic) piperidine (f) (614 mg, 2.66 mmol) and vinylquinoline (53h) (500 mg, 2.42 mmol) in dry DMF (5.0 mL) was stirred at90° C. After 48 hours, the solution was concentrated and chromatographedon silica gel eluting with 3% MeOH in DCM with 1% NH₄OH to afford theproduct as a yellow oil (560 mg, 50%).

MS (+ve ion electrospray) m/z 417 (M+H)⁺.

(h) Title Compound

Carbamate (g) (175 mg, 0.42 mmol) was deprotected giving thehydrochloride salt using the same procedure as used in Example (119)

MS (+ve ion electrospray) m/z 316 (M+H)⁺.

A solution of the above salt in dichloromethane and ethanol (6 mL) at25° C. were added N,N-diisopropylethylamine (731 μL, 4.20 mmol), Na₂SO₄(94 mg, 0.662 mmol) and aldehyde (7d) (89 mg, 0.42 mmol). After 12hours, sodium borohydride (25 mg, 0.504 mmol) was added and the reactionstirred an additional 2 hours, was concentrated and chromatographed onsilica gel eluting with 3% MeOH in DCM with 1% NH₄OH to afford the freebase of the title compound as a yellow solid (100 mg, 37%).

¹H NMR (CD₃OD, 500 MHz) δ 8.64 (s, 1H), 8.21 (d), 7.68 (d, 1H), 7.19 (d,1H), 7.03 (d, 1H), 4.12 (s, 3H), 3.82 (m, 2H), 3.53 (s, 2H), 3.33-3.45(m, 2H), 3.00-3.03 (m, 1H), 2.78-2.81 (m, 3H), 2.32-2.39 (m, 1H),2.12-2.13 (m, 1H), 2.01-2.04 (m, 1H), 1.93-1.96 (m, 1H), 1.22-1.26 (m,1H), 1.08 (s, 3H). MS (+ve ion electrospray) m/z 513 (M+H)⁺.

This material, as a solution in MeOH, was treated with an excess of 4MHCl in dioxane and evaporated to dryness to provide the title compound.

Subsequent to this work, Example (120e) has been resolved:—

Enantiomeric resolution of(+/−)-trans-2-(trimethylsilyl)ethyl-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-hydroxy-3-methyl-1-piperidinecarboxylateby chiral HPLC

(+/−)-trans-2-(trimethylsilyl)ethyl-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-hydroxy-3-methyl-1-piperidinecarboxylate(1.8 g) was dissolved in 50 mL of acetonitrile and applied to a columnof ChiralPak AD (77×240 mm, 20 u). Elution with acetonitrile: isopropylalcohol (95:5) was carried out at a flowrate of 300 mL/min, and uvdetection at 220 nm to yield the separate enantiomers:

Isomer E1 (0.77 g) alpha D +13.6° (c=1, CH₃OH); chiral purity >98% eewith retention time 2.4 min on analytical HPLC [Chiralpak AD 4.6×150 mm,10 u, acetonitrile: isopropyl alcohol (95:5), 1.0 mL/min, uv 205 nm].

Isomer E2 (0.78 g) alpha D −13.30 (c=1, CH₃OH); chiral purity >98% eewith retention time 3.1 min on analytical HPLC [Chiralpak AD 4.6×150 mm,10 u, acetonitrile: isopropyl alcohol (95:5), 1.0 mL/min, uv 205 nm].

The following racemic example was prepared by analogous methods toExample 120 using the aldehyde shown below:

Example 121 Trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-methyl-3-piperidinol dihydrochloride

Aldehyde is 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7- carbaldehyde as inexample (2c)

Example 1226-{[trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E1 (a)4-methyl-1-(phenylmethyl)-1,2,3,6-tetrahydropyridine

4-methylpyridine (10 g, 0.107 mmol) and benzyl chloride (12 mL, 0.107mmol) were combined at 25° C. and stirred 24 hours The resulting saltwas washed several times with Et₂O and used without furtherpurification.

MS (+ve ion electrospray) m/z 184 (M+H)⁺.

The above salt (15 g, 68.3 mmol) in EtOH (100 mL) was added dropwise toa solution of sodium borohydride (10 g, 0.273 mol) in ethanol (235 mL)at 0° C. The resulting suspension gradually warmed to 25° C. over 12hours, was concentrated and partitioned between water anddichloromethane. The aqueous phase was washed several times with DCM andthe combined organic fractions were dried (Na₂SO₄), concentrated andchromatographed on silica gel yielding the product as an orange oil(12.8 g, quant.).

MS (+ve ion electrospray) m/z 188 (M+H)⁺.

(b) Methyl 4-methyl-3,6-dihydro-1 (2H)-pyridinecarboxylate

To a solution of tetrahydropyridine (a) (6 g, 32.1 mmol) in dry toluene(32 mL) at 25° C. was added dropwise a solution of methyl chloroformate(5 mL, 64.1 mmol). After 12 hours at 80° C. the resulting solution wasconcentrated and chromatographed on silica gel eluting with 10% MeOH inDCM to afford the product as an orange oil (5.8 g, >quant. contaminatedwith residual benzyl chloride) that was used without furtherpurification.

MS (+ve ion electrospray) m/z 156 (M+H)⁺.

(c) Methyl 6-methyl-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate

To a solution of tetrahydropyridine (b) (1.0 g, 6.4 mmol) in drydichloromethane (21 mL) at 0° C. was added m-chloroperbenzoic acid (1.3g, 7.7 mmol) batchwise. After stirring 12 hours at 25° C., the solutionwas partitioned between 1N NaOH-DCM and the aqueous phase was backextracted several times with dichloromethane. The combined organicfractions were dried (Na₂SO₄), concentrated and chromatographed onsilica gel eluting with 1% MeOH in DCM yielding the product as a clearoil (1.0 g, 91%).

MS (+ve ion electrospray) m/z 172 (M+H)⁺.

(d)(+/−)-trans-methyl-4-amino-3-hydroxy-4-methyl-1-piperidinecarboxylate

To a refluxing solution of trimethylsilyl cyanide (4.6 mL, 34.3 mmol),ZnI₂ (273 mg, 0.857 mmol) in dry dichloromethane (171 mL) was addedepoxide (96c) (3.0 g, 17.13 mmol). After 12 hours the solution wascooled, concentrated and chromatographed on silica gel eluting withdichloromethane yielding the isonitrile as a yellow oil which was usedwithout further purification.

MS (+ve ion electrospray) m/z 273 (M+H)⁺.

To the above isonitrile in dry MeOH (100 mL) was added excess 4M HCl indioxane (18 mL, 71.6 mmol). After 1 hour, the solution was concentrated,the residue was taken up in MeOH and excess N,N-diisopropylethyl aminewas added to neutralise the salt. The solution was concentrated andchromatographed on silica gel eluting with 9% MeOH-1% NH₄OH in DCMyielding the product as a white solid (2.0 g, 74%).

MS (+ve ion electrospray) m/z 189 (M+H)⁺.

Enantiomeric resolution of(+/−)-trans-methyl-4-amino-3-hydroxy-4-methyl-1-piperidinecarboxylate bychiral HPLC

(+/−)-trans-methyl-4-amino-3-hydroxy-4-methyl-1-piperidinecarboxylate(1.0 g) was dissolved in 100 mL of acetonitrile:isopropylalcohol:isopropylamine (85:15:0.1) and applied to a column of ChiralPakAD (77×240 mm, 20 u). Elution with acetonitrile: isopropylalcohol:isopropylamine (85:15:0.1) was carried out at a flowrate of 300mL/min, and uv detection at 220 nm to yield the separate enantiomers:

Isomer E1 (0.41 g) alpha D −8.8° (c=1, CH₃OH); chiral purity >99% eewith retention time 2.8 min on analytical HPLC (Chiralpak AD 4.6×150 mm,10 u, acetonitrile: isopropyl alcohol:isopropylamine (85:15:0.1), 1.0mL/min, uv 205 nm].

Isomer E2 (0.40 g) alpha D +9.1° (c=1, CH₃OH); chiral purity >99% eewith retention time 3.7 min on analytical HPLC [Chiralpak AD 4.6×150 mm,10 u, acetonitrile: isopropyl alcohol:isopropylamine (85:15:0.1), 1.0mL/min, uv 205 nm].

(e) trans-4-amino-4-methyl-3-piperidinol

A solution of piperidinecarboxylate (d, Isomer E1) (1.0 g, 5.32 mmol) inethanol (12 mL) and 1N NaOH (16 mL) was stirred at reflux. After 12hours, the solution was concentrated and the residue was extracted withMeOH. The organic fractions were concentrated and chromatographed onsilica gel eluting with 9% MeOH, 1% NH₄OH in DCM affording the productas a clear oil (691 mg, quant.).

MS (+ve ion electrospray) m/z 131 (M+H)⁺.

(f)trans-4-amino-4-methyl-1-{3-fluoro-2-[6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinol

A solution of piperidinol (e, Isomer E1) (384 mg, 2.95 mmol) andvinyl-naphthyridine (53h) (450 mg, 2.21 mmol) in dry DMF (5.0 mL) wasstirred at 90° C. After 12 hours, the solution was concentrated andchromatographed on silica gel eluting with 6% MeOH in DCM with 1% NH₄OHaffording the product as a yellow oil (425 mg, 50%).

MS (+ve ion electrospray) m/z 317 (M+H)⁺.

(g) Title Compound

A solution of amine (f, Isomer E1) (175 mg, 0.552 mmol), aldehyde (7d)(89 mg, 0.552 mmol) and Na₂SO₄ (94 mg, 0.662 mmol) in DCM-EtOH (1:1, 6mL) was stirred for 12 hours. Sodium borohydride (25 mg, 0.662 mmol) wasadded and the solution stirred an additional 2 hours. The reactionmixture was concentrated and chromatographed on silica gel eluting with5% MeOH in DCM with 1% NH₄OH affording the free base of the titlecompound as a yellow solid (100 mg, 37%)

¹H NMR (CD₃OD, 400 MHz), δ 8.66 (s, 1H), 8.22 (d, 1H), 7.69 (d, 1H),7.20 (d, 1H), 7.05 (d, 1H), 4.14 (s, 3H), 3.83 (AB quartet, 2H),3.73-3.75 (m, 1H), 3.48-3.52 (m, 4H), 3.04-3.06 (m, 1H), 2.90-2.93 (m,1H), 2.85-2.87 (m, 2H), 2.35-2.49 (m, 2H), 1.70-1.73 (m, 2H), 1.18 (s,3H).

MS (+ve ion electrospray) m/z 513 (M+H)⁺.

This material, as a solution in MeOH, was treated with an excess of 4MHCl in dioxane and evaporated to dryness to provide the title compound.

The following example was prepared by analogous methods to Example 122:

Example RHS 123Trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-3-piperidinol dihydrochloride

Aldehyde is 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7- carbaldehyde as inexample (2c)

Example 1246-{[trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E2 (a) trans-4-amino-4-methyl-3-piperidinol

A solution of piperidinecarboxylate (122d—Isomer E2) (1.0 g, 5.32 mmol)in ethanol (12 mL) and 1N NaOH (16 mL) was stirred at reflux. After 12hours, the solution was concentrated and the residue was extracted withMeOH. The organic fractions were concentrated and chromatographed onsilica gel eluting with 9% MeOH, 1% NH₄OH in DCM affording the productas a clear oil (691 mg, quant.).

MS (+ve ion electrospray) m/z 131 (M+H)⁺.

(b)trans-4-amino-4-methyl-1-{2-[6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinol

A solution of piperidinol (e, Isomer E2) (384 mg, 2.95 mmol) andvinyl-naphthyridine (53h) (450 mg, 2.21 mmol) in dry DMF (5.0 mL) wasstirred at 90° C. After 12 hours, the solution was concentrated andchromatographed on silica gel eluting with 6% MeOH in DCM with 1% NH₄OHaffording the product as a yellow oil (425 mg, 50%).

MS (+ve ion electrospray) m/z 317 (M+H)⁺.

(c) Title Compound

A solution of amine (b, Isomer E2) (175 mg, 0.552 mmol), aldehyde (7d)(89 mg, 0.552 mmol) were treated as in example (123g) to afford the freebase of the title compound in a 60% yield.

¹H NMR (CD₃OD, 400 MHz), δ 8.66 (s, 1H), 8.22 (d, 1H), 7.69 (d, 1H),7.20 (d, 1H), 7.05 (d, 1H), 4.14 (s, 3H), 3.83 (AB quartet, 2H),3.73-3.75 (m, 1H), 3.48-3.52 (m, 4H), 3.04-3.06 (m, 1H), 2.90-2.93 (m,1H), 2.85-2.87 (m, 2H), 2.35-2.49 (m, 2H), 1.70-1.73 (m, 2H), 1.18 (s,3H).

MS (+ve ion electrospray) m/z 513 (M+H)⁺.

This material, as a solution in MeOH, was treated with an excess of 4MHCl in dioxane and evaporated to dryness to provide the title compound.

The following example was prepared by analogous methods to Example 124,using the aldehydes shown below:

Example 125 Trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-3-piperidinol dihydrochloride

Aldehyde is 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7- carbaldehyde as inexample (2c)

Example 126N-(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinaminedihydrochloride (a)[4-(3-hydroxy-1-propyn-1-yl)-5-({[4-(methoxy)phenyl]methyl)oxy)-2-pyridinyl]methylacetate

A mixture of triflate (60d) (1.0 g, 2.3 mmol), propynol (0.15 mL, 2.5mmol), copper diodide (22 mg, 0.125 mmol), palladiumdichloro-bis-triphenylphosphine (II) (32 mg, 0.046 mmol), triethylamine(5.7 mL, 41.4 mmol) in acetonitrile (30 mL) was stirred at 50° C. forone hour. A further equivalent of propynol was added and the reactionmixture was stirred at 50° C. for a further 18 hours. The reactionmixture was evaporated under vacuum to dryness. The residue waspartionned between ethyl acetate and a 0.1 M solution of sodiumethylenediamineacetate. The organic layer was washed with water anddried over sodium sulfate. The residue was chromatographed on silica geleluting with 25-100% ethyl acetate in 40-60 petroleum ether to affordthe product as on oil (0.48 g, 61%).

MS (+ve ion electrospray) m/z 342(MH+).

(b) [5-hydroxy-4-(3-hydroxypropyl)-2-pyridinyl]methyl acetate

A solution of alkyne (a) (3.3 g, 7.7 mmol) in ethanol (100 mL) washydrogenated in a Parr under 3 atmospheres of hydrogen with palladium oncharcoal for 6 hours. The reaction mixture was filtered throughKieselguhr and washed several times with ethanol then evaporated todryness under vacuum to afford the product as a white solid (2.17 g,100%).

MS (+ve ion electrospray) m/z 226(MH+).

(c) 3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl acetate

A mixture of triphenylphosphine (4.92 g, 18.8 mol) anddiisopropylazidicarboxylate (3.74 mL, 18.8 mol) in tetrahydrofuran (100mL) was stirred under argon for 1 hour. A solution of diol (b) (2.12 g,9.38 mmol) in tetrahydrofuran was added and the reaction mixture wasstirred at room temperature for 2 hours. It was evaporated under vacuum.The residue was chromatographed on silica gel eluting with 25-50% ethylacetate in petroleum ether then with 50-75% ethyl acetate to afford theproduct as a yellow oil (1.42 g, 60%).

MS (+ve ion electrospray) m/z 208 (MH+).

(d) 3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethanol

A solution of acetate (c) (1.52 g, 5.85 mmol) in tetrahydrofuran/water1/1 (40 mL) was treated with a 2N solution of sodium hydroxide (5.9 mL,11.7 mmol). The reaction mixture was stirred at room temperature for 2hours. The reaction mixture was saturated with potassium carbonate andextracted several times with ethyl acetate. The combined organicextracts were dried over magnesium sulfate and evaporated under vacuumto afford the product as an oil (1.22 g, 100%).

MS (+ve ion electrospray) m/z 166 (MH+).

(e) 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde

Alcohol (d) (1.22 g) was oxidised with manganese(II)oxide as in Example(2c) to afford the aldehyde as a white solid (0.532 g, 60%).

MS (+ve ion electrospray) m/z 164 (MH+).

(f) Title Compound

A mixture of the hydrochloride salt of amine (53i) (prepared fromdeprotection with HCl instead of TFA, according to the procedure ofExample 113b) (130 mg, 0.35 mmol) and aldehyde (e) (57 mg, 0.35 mmol) inmethanol (8 mL) was treated with sodium bicarbonate (319 mg, 1.73 mmol)at room temperature. The reaction was allowed to stir at roomtemperature for 18 hours. Sodium borohydride (13 mg, 0.35 mmol) wasadded, the mixture was continuously stirred for 1 hour at roomtemperature. Methanol was removed under reduced pressure and the residuewas partitioned between ethyl acetate and water. The organic layer wasseparated, washed with aqueous sodium chloride, dried over magnesiumsulfate and concentrated under reduced pressure. The residue waschromatographed on silica gel eluting with 0-10% methanol indichloromethane to afford the free base of the product as a solid. (97mg, 64%).

¹H NMR (CD₃OD, 400 MHz): 8.48 (s, 1H), 8.1 (d, 1H), 7.8 (s, 1H), 7.05(dd,s, 2H), 4.1 (m, 2H), 4.0 (s, 3H), 3.6(s, 2H), 3.3(m, 2H), 3.0 (m,2H), 2.7-2.8(m, 4H), 2.4(m, 1H), 2.1(m,3H), 1.8-1.9(m, 3H), 1.3(m, 2H)

MS (+ve ion electrospray) m/z 452 (MH+).

Example 127{[(1-{2-[3-Fluoro-6-(methoxy-5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-3,4-dihydro-1,8-naphthyridin-2-(1H)-one(a) Methyl6-amino-5-[(1E)-3-(ethyloxy)-3-oxo-1-propen-1-yl]-2-pyridinecarboxylate

A mixture of palladium acetate (211 mg, 0.23 mmol), tri-tolylphosphite(280 mg, 0.92 mmol) and triethylamine (3.18 mL, 23 mmol) were stirred atroom temperature for 30 minutes in degassed DMF. Methyl6-amino-5-bromopyridine-2-carboxylate (T. R. Kelly and F. Lang, J. Org.Chem. 61, 1996, 4623-4633) (58 mg, 4.60 mmol) was added followed byethyl acrylate (2.49 mL, 23 mmol). The resultant solution was stirred at100° C. for 18 hours. The reaction mixture was cooled down to roomtemperature and filtered through Kieselguhr. DMF was evaporated undervacuum and the residue was chromatographed on silica gel eluting with25-50% petroleum ether in ethyl acetate to afford the product as an oil(360 mg, 31%).

MS (+ve ion electrospray) m/z 251 (MH+).

(b) methyl 6-amino-5-[3-(ethyloxy)-3-oxopropyl]-2-pyridinecarboxylate

A solution of acrylate ester (a) (350 mg, 1.41 mmol) in methanol (50 mL)was hydrogenated with palladium on charcoal for 18 hours. The reactionmixture was filtered through Kieselguhr and evaporated under vacuum toafford the product as an oil (345 mg, 97%).

MS (+ve ion electrospray) m/z 253 (MH+).

(c) methyl 7-oxo-1,5,6,7-tetrahydro-1,8-naphthyridine-2-carboxylate

A solution of amino ester (b) (360 mg, 1.4 mmol) in acetic acid (20 mL)was heated to 100° C. for 1 hour. Acetic acid was evaporated in vacuoand the residue dried under high vacuum for 18 hours to afford a yellowsolid (361 mg, 100%).

MS (+ve ion electrospray) m/z 207 (MH+).

(d) 7-oxo-1,5,6,7-tetrahydro-1,8-naphthyridine-2-carboxylic acid

A solution of carboxylate (c) (355 mg, 1.72 mmol) in dioxan (5 mL)/water(1 mL) was treated dropwise with 2M NaOH solution (1 mL) and stirred for1 hour. After evaporation to approx. 2 mL, water was added and 2N HCl topH4. The precipitated solid was filtered off, washed with a small volumeof water and dried under vacuum to give the product as a solid (263 mg,79%).

MS (+ve ion electrospray) m/z 193 (MH+).

(e) 7-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

A solution of carboxylic acid (d) (293 mg, 1.53 mmol) in dichloromethane(5 mL)/tetrahydrofuran (5 mL) with triethylamine (466 mg, 3.36 mmol) wascooled to −10° C. and isobutyl chloroformate (0.218 mL, 1.68 mmol)added. After 20 minutes the suspension was filtered through Kieselguhrinto an ice-cooled solution of sodium borohydride (110 mg, 4.59 mmol) inwater (1 mL), the mixture was stirred 30 minutes and the pH reduced to 7with dilute hydrochloric acid. The solvent was evaporated and theresidue triturated under water. The residue was filtered and dried undervacuum to afford the product as a white solid (262 mg, 96%).

MS (+ve ion electrospray) m/z 179 (MH+).

(f) 7-oxo-1,5,6,7-tetrahydro-1,8-naphthyridine-2-carbaldehyde

Alcohol (e) was treated as in example (2c) to afford the product as awhite solid (72.2 mg, 28%).

MS (+ve ion electrospray) m/z 177 (MH+).

(g) Title Compound

A solution of amine (53i) (0.257 mg, 0.624 mmol) and solid sodiumbicarbonate (262.1 mg, 3.12 mmol) in methanol (2.8 mL) was stirred atroom temperature for 5 minutes. Dichloromethane (2.8 mL), aldehyde (f)(116 mg, 0.661 mmol) and sodium sulfate (710 mg, 5.0 mmol) were addedand the reaction mixture was stirred at room temperature for 24 hours.The intermediate imine was treated with sodium triacetoxyborohydride(0.263.3 mg, 2.05 mmol) and stirred for an additional 48 hours. Thereaction was acidified to pH 3 with 6N HCl, then stirred for 10 minutes.The solvents were removed under reduced pressure and the residue waspartitioned between dichloromethane and aqueous sodium bicarbonate. Theorganic layer was dried over sodium sulfate and evaporated under vacuum.The residue was chromatographed on silica gel eluting with 1-5% methanolin dichloromethane to afford the title compound as an amorphous yellowsolid (92.1 mg, 32%).

1H NMR δ (CDCl₃) 8.62 (1H, s), 8.22 (1H, bs), 8.17 (1H, d), 7.42 (1H,d), 7.06, (1H, d), 6.94 (1H, d), 4.08 (3H, s), 3.84 (2H, s) 3.41 (2H,t), 3.06 (2H, bd), 2.93 (2H, t), 2.75 (2H, t), 2.65 (2H, t), 2.55 (1H,m), 2.20 (2H, bt), 2.05 (1H, bs) 1.94, (2H, bd), 1.51 (2H, m)

MS (ES) m/z 465.4 (M+H)⁺.

Example 1287-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-2,3-dihydro-1,5-benzothiazepin-4(5H)-one(a) Methyl 4-([3-(methoxy)-3-oxopropyl]thio}-3-nitrobenzoate

To a solution of methyl 4-chloro-3-nitrobenzoate (4.53 g, 0.021 mol) andmethyl 3-mercaptopropionate (2.78 g, 0.023 mol) in dimethylformamide (15mL) was added anhydrous potassium carbonate (0.023 mol, 3.17 g). Afterstirring at ambient temperature for 16 hours, the reaction was quenchedwith ice water. The precipitated product was filtered, washed well withwater and dried under vacuum to give a bright yellow solid (6.11 g,97%).

MS (ES) m/z 300.2. (M+H)⁺.

(b) Methyl 3-amino-4-{[3-(methoxy)-3-oxopropyl]thiobenzoate

To a solution of nitrobenzoate (a) (7.58 g, 0.025 mol) in glacial aceticacid (186 mL) was added iron powder (14.0 g, 0.250 mol). After heatingat 75° C. for 6 hours, the warm mixture was filtered and the filtrateconcentrated under reduced pressure. The residue was partitioned betweenethyl acetate and aqueous sodium chloride, and the organic layer wasdried over magnesium sulfate. Filtration and evaporation afforded theproduct (7.03 g, 100%) which was used without further purification.

MS (ES) m/z 270.2. (M+H)⁺.

(c) Methyl 4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxylate

A suspension of ester (b) (3.00 g, 0.011 mol) in Decalin™ (120 ml) washeated at 160° C. for 40 hours. The reaction was allowed to cool and theprecipitate was collected by filtration. The solid was dissolved in 1:1acetone: methanol mixture and treated with decolorizing carbon. Thesolvent was evaporated in vacuo to afford a tan solid (1.67 g, 73%)

MS (ES) m/z 238.0. (M+H)⁺.

(d) 7-(Hydroxymethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one

To a solution of the ester (c) (300 mg, 1.27 mmol) in tetrahydrofuran (7mL) was added lithium borohydride (55.2 mg, 2.52 mmol) at 0° C. Thereaction was stirred at room temperature for 16 hours, then quenchedwith methanol. The reaction was stirred for 20 minutes, then thesolvents removed under reduced pressure. The residue was partitionedbetween ethyl acetate and aqueous sodium chloride, and the organic layerwas dried over magnesium sulfate. The solvent was evaporated in vacuo toafford a semisolid mass which was triturated with cold acetonitrile togive the product as an off-white solid (95 mg, 35%).

MS (ES) m/z 210.0. (M+H)⁺.

(e) 4-Oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]thiazepine-7-carboxaldehyde

To a solution of alcohol (d) (92 mg, 0.44 mmol) in 1:6 dichloromethane:ethyl acetate (35 mL) was added Dess-Martin periodinane (242 mg, 0.57mmol). The reaction was stirred at room temperature for 1.5 hours, thenquenched with a cold aqueous 1N solution of sodium hydroxide. The layerswere separated and the organic layer was washed with a 0.5 N solution ofsodium hydroxide, brine and dried over sodium sulfate. The solvent wasevaporated in vacuo to afford the product as an off-white solid (72 mg,79%).

MS (ES) m/z 208.0 (M+H)⁺.

(f) Title Compound

Amine (53i) and aldehyde (e) were treated as in Example (128) to affordthe product as an amorphous light yellow solid in a 20% yield

1H NMR δ (CDCl₃) ¹H NMR δ (CDCl₃) 8.61 (1H, s), 8.17 (1H, d), 7.52 (1H,d), 7.43, (1H, bs), 7.13, (1H, d), 7.08 (1H, s), 7.07 (1H, d), 4.08 (3H,s), 3.82 (2H, s) 3.42 (4H, apparent q), 3.06 (2H, bd), 2.7 (2H, m), 2.62(2H, t), 2.52 (1H, m), 2.18 (2H, bt), 1.93, (2H, bd), 1.50 (1H, bs),1.45 (2H, m).

MS (ES) m/z 496.4 (M+H)⁺.

Example 129trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinoldihydrochloride Enantiomer E1 (a) 1,1-dimethylethyl((trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)carbamate

The vinyl naphthyridine (53h) (1.25 g, 6.1 mmole) was heated to 100° C.together with trans-1,1-dimethylethyl (3-hydroxy-4-piperidinyl)carbamate(prepared by hydrogenation of Example 17f, Isomer E1) (1.32 g, 6.1mmole) in DMF (5 mL). After 24 hours, the mixture was concentrated invacuo and purified on silica (CHCl₃/MeOH with 5% NH₄OH, 9:1) to give theproduct as an oil (1.9 g, 75%).

MS (ES) m/z 421 (M+H)⁺.

(b) Title Compound

To a solution of carbamate (a) (1.9 g, 4.57 mmole) in dichloromethane(100 mL) was added 4M HCl in dioxane (20 mL). After stirring for 3 h,the reaction was evaporated to give a white solid which was used withoutfurther purification (98%).

MS (ES) m/z 321 (M+H)⁺.

To a solution of the above hydrochloride salt (ca 1.0 mmole) in ethanol(20 mL) and dichloromethane (20 mL) was added triethyl amine (0.56 mL,4.0 mmole) and aldehyde (2c) (0.17 g, 1.0 mmole). After 24 hours at roomtemperature, sodium borohydride (42 mg, 1.1 mmole) was added and thereaction mixture stirred for 5 hours. Silica gel (−2 g) was added to themixture and the reaction contents stirred for an additional 2 hours. Thereaction slurry was concentrated to dryness in vacuo and loaded onto asilica gel column (eluting with CHCl₃/MeOH containing 5% NH₄OH, 9:1) toafford the free base of the title compound as a white foam.

This material, as a solution in chloroform/methanol, was treated with anexcess of 2M HCl in ether and evaporated to dryness. The solid wastriturated with ether, filtered and dried under vacuum to provide thetitle compound (71%) as a white solid.

¹H NMR of the dihydrochloride salt δH (CD₃OD) 8.82 (1H, s), 8.48(1H, s),8.31 (1H, d), 7.59 (1H, s), 7.29 (1H, d), 4.65 (4H, m), 4.51 (2H, m),4.40 (1H, m), 4.21 (3H, s), 3.97 (1H, m), 3.89 (1H, m), 3.80 (2H, m),3.63 (4H, m), 3.19 (1H, m), 2.64 (1H, s), 2.30 (1H, m).

MS (+ve ion electrospray) m/z 470 (M+H)⁺.

The following example was prepared by analogous methods to Example 129using the aldehyde shown below:

Example 130 6-{[(-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one dihydrochloride

Aldehyde is 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde as in example (1l)

Example 131trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one—EnantiomerE1

This was prepared from vinyl quinoline Example (31e) using themethodology of Examples 17 (enantiomer 1 series) affording the free baseodf the title compound.

¹H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.90 (d, 1H), 7.45 (d, 1H), 7.22(dd, 1H), 7.10 (s, 1H), 6.81 (d, 1H), 3.95 (d, 1H), 3.85 (s, 3H), 3.77(d, 1H), 3.59 (m, 1H), 3.31 (s, 2H), 3.21 (dd, 1H), 3.14 (t, 2H), 2.95(d, 1H), 2.63 (m, 2H), 2.39 (m, 1H), 2.10 (m, 1H), 2.07 (m, 1H), 2.04(m, 1H), 1.94 (m, 1H), 1.46 (m, 1H).

MS (ES) m/z 498 (M+H)⁺.

The title compound was then prepared by dissolving the product inchloroform and adding 2 equivalents of HCl/ether. The mixture wasstirred for 15 minutes and the solvent removed under reduced pressureyielding an off white solid (0.191 g).

The following examples were prepared by analogous methods to Example131:

Example 132 trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3- piperidinoldihydrochloride

Aldehyde is 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7- carbaldehyde as inexample (2c) 133trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one dihydrochloride

Aldehyde is 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde as in example (1l)

Example 134trans-N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamidehydrochloride Enantiomer E1

Piperidinol hydrochloride salt Isomer E1 {prepared as in Example (129b)}and carboxylic acid (7b) were treated as in Example (118) to afford thefree base of the title compound as a white solid.

This material, as a solution in chloroform/methanol, was treated with anexcess of 2M HCl in ether and evaporated to dryness. The solid wastriturated with ether, filtered and dried under vacuum to provide thetitle compound (85%) as a white solid.

¹H NMR of the dihydrochloride salt δH (CDCl₃) 8.61 (1H, s), 8.19 (1H,d), 7.79 (2H, m), 7.31 (1H, d), 7.10 (1H, d), 4.50 (1H, m), 4.15 (3H,s), 3.65-3.89 (4H, m), 3.42 (3H, m), 3.09 (2H, s), 2.92 (2H, m), 2.47(1H, m), 2.11 (1H, m).

MS (+ve ion electrospray) m/z 513 (M+H)⁺.

The following examples were prepared by analogous method to Example 134using the acids shown below:

Example RHS 135 trans-N-((3R,4R)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxamide Isomer E1hydrochloride

3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxylic acid wasprepared as in example (65) 136trans-N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-2,3-dihydro[1,4]di-oxino[2,3-c]pyridine-7-carboxamide Isomer E1_hydrochloride

2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxylic acid is as inexample (119a)

Example 1376-{[trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-oneEnantiomer E1

This compound was prepared by the same methodology and exhibited thesame spectroscopic properties (NMR and MS) as the enantiomeric analogue(Example 113, Isomer E2).

Example 1386-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride (a) 1-(1,1-dimethylethyl) 4-methyl1,4-piperidinedicarboxylate

To a stirred solution of methyl-4-piperidinecarboxylate (10 g, 0.070mol) in dioxane (140 mL) was added triethylamine (14.6 mL, 0.105 mol)and di-t-butyl-dicarbonate (19 g, 0.087 mol). The reaction mixture wasstirred at ambient temperature for 96 hours. The solution wasconcentrated in vacuo. The residue was taken up in ethyl acetate (300mL) and washed with brine solution (2×200 mL). The organic layer wasobtained, dried over sodium sulfate, and concentrated to afford thetitle compound (17 g, 98%) as a yellow oil.

(b) 1-(1,1-dimethylethyl) 4-methyl 4-methyl-1,4-piperidinedicarboxylate

An oven-dried flask equipped with a stirring bar and rubber septum wascharged with anhydrous THF (100 mL) and placed under a stream ofnitrogen. Diisopropylamine (6.34 mL, 0.0452 mol) was added and thesolution cooled to −78° C. To the cooled solution was addedn-butyllithium (1.6 M in hexanes, 28 mL, 0.0452 mol) over 5 minutes. Thereaction mixture was stirred for 30 minutes then

(a) (10 g, 0.0411 mol) was added and the mixture stirred for anadditional hour.

After 1 hour methyl iodide (3.07 mL, 0.0493 mol) was added and stirredfor 1.5 hours. The reaction mixture was quenched with brine andconcentrated in vacuo. The residue was taken up in ethyl acetate (250mL) and washed with saturated NaHCO₃ (2×150 mL) and brine (2×100 mL).The organic layer was dried over sodium sulfate and concentated invacuo. The crude product was purified by silica gel columnchromatography eluting with 20% ethyl acetate/hexanes to obtain thetitle compound (7.95 g, 95%) as a pale yellow oil.

LC-MS (ES) m/z 158.2 (M+H)_(t) (minus Boc).

(c) 1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-methyl-4-piperidinecarboxylicacid

To a round bottom flask was added (b) (7.6 g, 0.0295 mol) in 200 mL ofmethanol. To this solution was added a solution of 1N sodium hydroxide(29.5 mL, 0.0295 mol) and the mixture was heated to 45° C. for 18 hours.The reaction mixture was concentrated in vacuo. The residue wasdissolved in water (100 mL) and the pH carefully adjusted to −3 by theaddition of 1N HCl. The crude product was extracted into chloroform(3×300 mL), dried over sodium sulfate and concentrated in vacuo toobtain the title compound (5.86 g; 81%) as a light yellow oil whichsolidified upon standing.

(d) 1,1-dimethylethyl4-methyl-4-({[(phenylmethyl)oxy]carbonyl)amino)-1-piperidinecarboxylate

To an oven-dried round bottom flask equipped with a stirring bar and arubber septum was added (c) (3.5 g, 0.0144 mol) in anhydrous toluene(100 mL). To this mixture was added triethylamine (4 mL, 0.0288 mol) anddiphenylphosphoryl azide (6.2 mL, 0.0288 mol). The reaction was heatedto 85° C. under nitrogen for 2 hours then benzyl alcohol (3 mL, 0.0288mol) was added and the reaction mixture was stirred at 85° C. for 18hours. The reaction mixture was concentrated in vacuo andchromatographed on silica gel chromatography eluting with 20% ethylacetate/hexanes to provide the product as a colorless oil (3 g, 60%).

LC-MS (ES) m/z 249.4 (M+H)⁺ (minus BOC).

(e) phenylmethyl (4-methyl-4-piperidinyl)carbamate

To a round bottom flask equipped with a stirring bar was added (d) (3 g,0.0086 mol) in 50% trifluoroacetic acid in dichloromethane (100 mL).After 30 minutes, the reaction mixture was concentrated in vacuo and 100mL of saturated NaHCO₃ was added and the product extracted intodichloromethane (2×100 mL). The organic layer was dried over sodiumsulfate and concentrated to provide the product as a yellow oil (2 g,95%).

LC-MS (ES) m/z 249.4 (M+H)⁺.

(f) Phenylmethyl(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)carbamate

A mixture of vinyl-naphthyridine (53h) (800 mg; 3.92 mmol), (e) (1.42 g;3.92 mmol), and triethylamine (1.09 mL; 7.84 mmol) in DMF (2 mL) washeated to 100° C. for 18 hours then concentrated in vacuo. The residuewas chromatographed on silica gel eluting with ethyl acetate to affordthe product as a brown oil (600 mg, 34%).

MS (+ve ion electrospray) m/z 453 (M+H)⁺.

(g)1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinamine

A solution of (f) (600 mg; 1.33 mmol) in ethanol (100 mL) washydrogenated under 1 atmosphere with palladium hydroxide on charcoal (60mg) for 18 hours. The reaction mixture was filtered through Kieselguhrand concentrated to afford the product as a yellow oil (380 mg, 90%)

MS (+ve ion electrospray) m/z 319 (M+H)⁺.

(h) Title Compound

The amine (g) and aldehyde (1l) were reacted together in a mannersimilar to that of Example (129b), using sodium borohydride as reducingagent, affording the free base of the title compound in 40% yield.

¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 1H), 8.10 (d, 1H), 7.10 (d, 1H), 6.90(d, 1H), 6.88 (d, 2H) 4.48 (s, 2H), 3.99 (s, 3H), 3.31 (s, 2H), 2.59 (m,6H), 1.67 (m, 4H), and 1.10 (s, 3H).

MS (+ve ion electrospray) m/z 481 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 2M HCl in ether and evaporated to dryness. The solid wastriturated with ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

The following examples were prepared by analogous method to Example 138using the aldehydes shown below:

Example 1396-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one dihydrochloride

Aldehyde is 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde as in example (7d) 140N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinamine dihydrochloride

Aldehyde is 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7- carbaldehyde as inexample (2c) 141 N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)-2,3-dihydro-1,4-benzodioxin-6-sulfonamide

2,3-dihydro-1,4-benzodioxin-6-sulfonyl chloride is commerciallyavailable and sulfonamide formation used triethylamine as amine base

Example 142cis-6-{[(1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer 1 (a)cis-4-Benzylamino-1-tert-butoxycarbonyl-3-fluoropiperidine

4-Benzyl-1-tert-butoxycarbonyl-3-fluoropiperidine was prepared accordingto the procedures of J. Med. Chem. 1999, 42, 2087-2104 as a mixture ofisomers (approx 8:1 cis:trans, 29.8 g, 0.096 mole). The mixture wasdissolved in DCM, extracted with 0.2M HCl, basified with Na₂CO₃solution, extracted with DCM and chromatographed on silica gel to givethe cis-isomer in the later fractions (15.6 g, 52%). Combined batches(32 g, 0.103 mole) were separated by preparative HPLC on a Chiralpak ADcolumn eluting with hexane:ethanol (9:1) to give faster runningenantiomer [Enantiomer 1] (15.09, 47%, 99% ee) [□]_(D) +40.5° and slowerrunning enantiomer [Enantiomer 2] (15.0 g, 47%, 97% ee) [□]_(D) −39.5°.

(b) cis-1,1-dimethylethyl 4-amino-3-fluoro-1-piperidinecarboxylate,Enantiomer 1

To a solution ofcis-4-benzylamino-1-tert-butoxycarbonyl-3-fluoropiperidine (a,Enantiomer 1) (29 g, 94 mmole) in EtOH (300 mL) was added palladiumhydroxide (8g). The reaction was hydrogenated for 6 hours, then wasfiltered through Kieselguhr. The filtrate was concentrated under reducedpressure to afford the title compound as a white solid (20.5 g, 100%).

MS (ES) m/z 219 (M+H)⁺.

(c) cis-1,1-dimethylethyl3-fluoro-4-({[(phenylmethyl)oxy]carbonyl}amino)-1-piperidinecarboxylate,Enantiomer 1

To a solution of amine (b, Enantiomer1) (23 g, 105 mmol) in ethylacetate (200 mL) was added a saturated solution of sodium bicarbonate(200 mL) followed by benzyl chloroformate (16 mL, 116 mmol). Thereaction mixture was stirred for 4.5 hours. The layers were separatedand the aqueous extraacted with ethyl acetate. The combined organicextracts were dried over magnesium sulfate and evaporated under vacuumto afford the product as an oil (37.4 g, 100%).

MS (ES) m/z 353 (M+H)⁺.

(d) cis-phenylmethyl (3-fluoro-4-piperidinyl)carbamate

The carbamate (c, Enantiomer 1) (37 g, 105 mmol) in dichloromethane (150mL) was treated with trifluoroacetic acid (60 mL) at room temperaturefor 4 hours. The residue was basified with sodium carbonate andextracted with 10% methanol-dichloromethane. The combined organicextracts were dried over magnesium sulfate and evaporated under vacuumto afford the product as a white solid (26.8 g, 100%).

MS (ES) m/z 253 (M+H)⁺.

(e) cis-phenylmethyl(1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)carbamate,Enantiomer 1

Vinyl-quinoline (97d) and fluoropiperidine (d, Enantiomer 1) weretreated as in example (52h) to afford the product as an oil in 25%yield.

MS (ES) m/z 490 (M+H)⁺.

(f)cis-1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinamine,Enantiomer 1

The carbamate (d, Enantiomer 1) (0.103 g, 0.2 mmol) in ethanol washydrogenated with 10% palladium on charcoal for 18 hours. The mixturewas filtered through Kieselguhr and evaporated under vaccum to affordthe product as an oil (26 mg, 35%).

MS (ES) m/356 (M+H)⁺.

(g) Title Compound

Amine (f, Enantiomer 1) and aldehyde (7d) were treated as in Example(53j) to afford the free base of the title compound as an oil in a 46%yield.

1H NMR δH (CDCl₃) 8.67 (1H, s) 8.34 (1H, bs), 7.59 (1H, d), 7.08 (3H,m), 4.86 (1H, d), 3.94 (3H, s) 3.91 (2H, s), 3.47 (2H, s), 3.37 (3H, m),3.07 (1H, d), 2.68 (3H, m), 2.43 (1H, dd), 2.29 (1H, m), 1.87 (3H, m).

MS (ES) m/z 534 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 2M HCl in ether and evaporated to dryness. The solid wastriturated with ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 143cis-1-{2-[3,8-difluoro-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-3-fluoro-4-piperidinaminedihydrochloride Enantiomer1

The free base of this compound was prepared by methods analogous tothose of Example (142) with the exceptions that the vinyl quinoline usedwas Example (47j) and the aldehyde used in the last stage was Example(2c).

1H NMR δH (CDCl₃) 8.61 (1H, s) 8.11 (1H, s), 7.04 (2H, m), 6.76 (1H, s),4.85 (1H, d), 4.31 (4H, m), 3.95 (3H, s) 3.87 (2H, s), 3.33 (1H, m),3.23 (2H, t), 3.04 (1H, d), 2.68 (3H, m), 2.43 (1H, dd), 2.23 (1H, m),1.86 (2H, m).

MS (ES) m/z 489 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 2M HCl in ether and evaporated to dryness. The solid wastriturated with ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 144cis-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-3-fluoro-4-piperidinaminedihydrochloride Enantiomer 2

This was prepared in an analogous way to Example 143, with the exceptionthat cis-4-benzylamino-1-tertbutoxycarbonyl-3-fluoropiperidine,Enantiomer 2 (Example 143a) was used as the starting material.Spectroscopic properties (NMR and MS) and salt formation was the same.

The following examples were prepared by analogous methods to Example 143using the aldehydes shown below:

Example 145cis-6-{[(1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one dihydrochloride, Enantiomer 1, 146cis-6-{[(1-{2-[3,8-difluoro-6-(methoxy)-4- quinolinyl]ethyl}-3-fluoro-4-piperidinyl)amino]methyl}-2H-pyrido[3,2- b][1,4]oxazin-3(4H)-onedihydrochloride, Enantiomer 2,

Aldehyde is 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde as in example (1l) 147cis-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-3-fluoro-4- piperidinaminedihydrochloride, Enantiomer 1 148 cis-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-3-fluoro-4-piperidinamine dihydrochloride, Enantiomer 2

Aldehyde is 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde- commerciallyavailable 149cis-6-{[(-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one dihydrochloride, Enantiomer 1 150cis-6-{[(-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4- piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one dihydrochloride, Enantiomer 2

Aldehyde is 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde as in example (7d)

Aldehyde is3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde as inexample (7d)

Example 151cis-N-(1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamidehydrochloride Enantiomer 1

Amine (142f) and carboxylic acid (7b) were treated as in Example (118)to afford the free base of the title compound as an oil in almost 100%yield.

1H NMR δH (CDCl₃) 8.63 (1H, s), 8.29 (1H, s), 7.91 (1H, d), 7.85 (1H,d), 7.79 (1H, d), 7.07 (1H, dd), 7.03 (1H, d), 4.80 (1H, d), 4.20 (1H,m), 3.96 (3H, s), 3.48 (2H, s), 3.54 (2H, m), 3.40 (1H, m) 3.25 (2H, t),3.14 (1H, d), 2.75 (2H, m), 2.49 (1H, dd), 2.38 (1H, t), 1.97 (1H, m),1.92 (1H, m).

MS (ES) m/z 532 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 2M HCl in ether and evaporated to dryness. The solid wastriturated with ether, filtered and dried under vacuum to provide thedihydrochloride salt of the title compound as a white solid.

Example 1526-{[((3S,4R)-1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E2 (a) 1,1-dimethylethyl((3S,4R)-1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)carbamate,Isomer E2

Vinyl-quinoline (97d) and 1,1-dimethylethyl[(3S,4R)-3-hydroxy-4-piperidinyl]carbamate (5c, Enantiomer 2) weretreated as in Example (47k) to afford the product as an oil in 33%yield.

MS (ES) m/z 454/456 (M+H)⁺.

(b)(3S,4R)-4-amino-1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-piperidinol,Enantiomer 1

Carbamate (a) was treated as in example (471) to afford the product as asolid in a 98% yield.

MS (ES) m/z 354/356 (M+H)⁺.

(c) Title Compound

Amine (b) and aldehyde (2c) were treated as in example (52j) to affordthe free base of the title compound as an oil in a 31% yield.

1H NMR δH (CDCl₃) 8.67 (1H, s), 8.10 (1H, s), 7.09 (1H, dd), 7.05 (1H,d), 6.81 (1H, s), 4.30 (4H, m), 3.94 (3H, s), 3.89 (1H, s), 3.83 (2H,s), 3.37 (2H, t), 3.14 (1H, d), 2.97 (1H, d), 2.65 (2H, m), 2.36 (1H,d), 2.25 (1H, m), 1.97 (1H, m), 1.75 (2H, m).

MS (ES) m/z 503/505 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 2M HCl in ether and evaporated to dryness. The solid wastriturated with ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 153trans-6-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one trihydrochloride Enantiomer 1

A solution of amine (41a) and aldehyde (1l) were treated as in Example(40) to afford the title compound as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.81 (s, 1H), 9.31 (s, 1H), 8.84 (s, 1H),8.33 (d, 1H,), 7.46 (d, 1H), 7.34 (d, 1H), 7.23 (d, 1H), 4.70 (s, 2H),4.38 (m, 7H), 4.12 (s, 3H), 3.81 (m, 3H), 3.56 (m, 1H), 3.43 (m, 3H),3.18 (m, 1H), 2.99 (m, 1H), 2.56 (m, 1H), 2.18 (m, 1H).

LC-MS (ES) m/z 499.4 (M+H)⁺.

Example 154trans-1-{2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinolEnantiomer 1

A solution of amine (41a) and aldehyde (2c) were treated as in Example(40) to afford the product as a white solid.

MS (ES) m/z 486 (M+H)⁺.

Example 155trans-1-{2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinolEnantiomer 2

A solution of amine (see Example 46) and aldehyde (2c) were treated asin Example (40) to afford the product as a white solid.

MS (ES) m/z 486 (M+H)⁺.

Example 1562-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}-1-[3-fluoro-6-(methoxy)-4-quinolinyl]ethanoldihydrochloride Enantiomer 1

This is the alternative enantiomer to Example (112, Enantiomer 2) andwas isolated by chiral preparative hplc as described in Example (99).The free base of the title compound was isolated as a white foam, as themajor, first eluting enantiomer.

1H NMR δH (400 mHz, CDCl₃) 8.56 (1H, s), 8.10 (1H, s), 7.95 (1H, d),7.92 (1H, d), 7.29 (1H, dd), 6.83 (1H, s), 5.58 (1H, dd), 4.25-4.35 (4H,m), 3.93 (3H, s), 3.81 (2H, s), 3.18 (1H, m), 3.03 (1H, m), 2.90 (1H,m), 2.60 (2H, m), 2.49 (1H, br.t), 2.18 (1H, br.t), 1.90 (2H, m), 1.80(2H, m), 1.40-1.65 (2H, m)

MS (ES) m/z 469 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid (70 mg).

Example 157N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinamine

Amine (53i) and 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde as in Example(148) were treated as in Example (53j) to afford the free base of thecompound.

¹H NMR (400 MHz, d₄-MeOH) 8.59 (s, 1H), 8.14 (d, 1H), 7.10 (d, 1H), 6.90(s, 1H), 6.79-6.85 (m, 2H), 4.07 (s, 3H), 4.22 (s, 4H), 3.84 (s, 2H),3.32-3.29 (m, 2H), 3.13-3.16 (m, 2H), 2.72-2.81 (m, 3H), 2.18-2.21 (m,2H), 2.12-2.05 (m, 2H), 1.51-1.60 (m, 2H).

MS (ES) m/z 453 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 158(3S,4R)-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinoldihydrochloride Enantiomer 2

Amine (70a) and aldehyde (2c) were treated as in Example (53j) to affordthe free base of the compound.

1H NMR δH (CDCl₃) 8.61 (1H, s), 8.17 (1H, d), 8.10 (1H, s), 7.07 (1H,d), 6.84 (1H, s), 4.20-4.35 (4H, m), 4.08 (3H, s), 3.87 (1H, s), 3.83(2H, s), 3.39 (2H, bt), 3.10 (1H, bd), 2.95 (1H, bd), 2.78 (2H, bt),2.50-2.60 (1H, m), 2.34 (1H, d), 2.22 (1H, bt), 1.6-1.9 (m, includingwater)

MS (ES) m/z 470 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 159 (3R,4S)1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-[([1,3]oxathiolo[5,4-c]pyridin-6-ylmethyl)amino]-3-piperidinoldihydrochloride Enantiomer E1

Amine (66b) and aldehyde (61) were treated as in Example (53j) to affordthe free base of the compound.

¹H NMR (400 MHz, CDCl3) 8.61 (s, 1H), 8.18-8.16 (d, 1H), 8.00 (s, 1H),7.26-7.23 (d, 1H), 7.08-7.06 (d, 1H), 5.74-5.73 (s, 2H), 4.08-3.88 (s,3H), 3.85 (s, 2H), 3.40-3.36 (m, 2H), 2.92-2.80 (m, 3H), 2.77-2.75 (m,2H), 2.53-2.51 (m, 1H), 2.34-2.20 (m, 2H), 1.72-1.60 (m, 4H).

MS (ES) m/z 472 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 1606-{[(1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one(a) 1,1-dimethylethyl(1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)carbamate

Vinyl-quinoline (98d) and piperidin-4-yl-carbamic acid tert-butyl esterwere treated as in Example (52h) to afford the product in 73% yield.

MS (ES) m/z 438/440 (M+H)⁺.

(b)1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinamine

Carbamate (a) was treated as in Example (66b) to afford the amine in aquantitative yield.

MS (ES) m/z 338/340 (M+H)⁺.

(c) Title Compound

Amine (b) and aldehyde (7d) were treated as in Example (53j) to affordthe free base of the compound.

1H NMR δH (CDCl₃) 8.67 (1H, s), 8.06 (1H, bs), 7.57 (1H, d), 7.09 (2H,dd), 6.99 (1H, d), 3.95 (3H, s), 3.85 (2H, s), 3.48 (2H, s), 3.39 (2H,m) 3.06 (2H, m), 2.70-2.52 (3H, m), 2.21 (2H, m), 1.96 (2H, d), 1.55(2H, m).

MS (ES) m/z 517 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 1611-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinamine

Amine (160b) and aldehyde (2c) were treated as in Example (53j) toafford the free base of the compound.

1H NMR δH (CDCl₃) 8.66 (1H, s) 8.11 (1H, s), 7.08 (2H, m), 6.83 (1H, s),4.33 (2H, m), 4.27(2H, m), 3.94 (3H, s), 3.81 (2H, s), 3.37 (2H, m),3.05 (2H, m), 2.68-2.51 (3H, m), 2.23 (2H, t), 2.20 (2H, d), 1.55 (2H,m).

MS (ES) m/z 487 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 162(3S,4R)-1-[2-(3,6-dichloro-4-quinolinyl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinoldihydrochloride Enantiomer E2 (a) 1,1-dimethylethyl((3S,4R)-1-[2-(3,6-dichloro-4-quinolinyl)ethyl]-3-hydroxy-4-piperidinyl)carbamate

Vinyl-quinoline (27e) and piperidine (5c, enantiomer E2) were treated asin Example (23g) to afford the product as an oil.

MS (ES) m/z 440 (M+H)⁺.

(b) (3S,4R)-4-amino-1-[2-(3,6-dichloro-4-quinolinyl)ethyl]-3-piperidinol

Carbamate (a) was treated as in Example (23h) to afford the product asan oil. MS (ES) m/z 340 (M+H)⁺.

(c) Title Compound

Amine (b) and aldehyde (2c) were treated as in Example (23i) to affordthe product as an oil. MS (ES) m/z 490 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 1636-[({(3S,4R)-1-[2-(3,6-dichloro-4-quinolinyl)ethyl]-3-hydroxy-4-piperidinyl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E2

Amine (162b) and aldehyde (7d) were treated as in Example (23i) toafford the product as an oil.

MS (ES) m/z 518 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 164(3S,4R)-1-[2-(3-chloro-6-fluoro-4-quinolinyl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinoldihydrochloride Enantiomer E2 (a) 1,1-dimethylethyl{(3S,4R)-1-[2-(3-chloro-6-fluoro-4-quinolinyl)ethyl]-3-hydroxy-4-piperidinyl}carbamate

Vinyl-quinoline (25e) and piperidine (5c, enantiomer E2) were treated asin Example (23g) to afford the product as an oil.

MS (ES) m/z 424 (M+H)⁺.

(b)(3S,4R)-4-amino-1-[2-(3-chloro-6-fluoro-4-quinolinyl)ethyl]-3-piperidinol

Carbamate (a) was treated as in Example (23h) to afford the product asan oil. MS (ES) m/z 324 (M+H)⁺.

(c) Title Compound

Amine (b) and aldehyde (2c) were treated as in Example (23i) to affordthe product as an oil.

MS (ES) m/z 473 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 1656-[({(3S,4R)-1-[2-(3-chloro-6-fluoro-4-quinolinyl)ethyl]-3-hydroxy-4-piperidinyl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E2

Amine (164b) and aldehyde (7d) were treated as in Example (23i) toafford the product as an oil.

MS (ES) m/z 502 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 166N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)-2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxamidedihydrochloride

Amine (138g) and carboxylic acid (119a) were treated as in Example (118)to afford the title compound.

MS (ES) m/z 482 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

The following Examples were prepared by analogous method to Example 134using the acids shown below:

Example 167 N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxamide

3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxylic acid wasprepared as in Example (65) 168N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide

3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid wasprepared as in Example (7b)

Example 169trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-3-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E1

Amine (120e, enantiomer E1) and aldehyde (1l) were treated as in Example(120h) to afford the title compound.

MS (ES) m/z 497 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 170trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-3-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E1

Amine (120e, enantiomer E1) and aldehyde (7d) were treated as in Example(120h) to afford the title compound.

MS (ES) m/z 513 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 171trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-3-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E2

Amine (120e, enantiomer E2) and aldehyde (1l) were treated as in Example(120h) to afford the title compound.

MS (ES) m/z 497 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 172trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-3-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E2

Amine (120e, enantiomer E2) and aldehyde (7d) were treated as in Example(120h) to afford the title compound.

MS (ES) m/z 513 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 173trans-4[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-piperidinolhydrochloride Enantiomer E1

This was prepared by hydrogenation of piperidine (17f, enantiomer E1)over Pearlman's catalyst by the method of Example (5c), followed byreaction with the vinyl-quinoline (31e), removal of BOC protecting groupand reaction with aldehyde (148) by the methods of Examples (5d-f) toafford the free base of the title compound.

MS (ES) m/z 468 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 174trans-4-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinoldihydrochloride Enantiomer E2

This was prepared by the method of Example (113) using aldehyde (148)instead of aldehyde (7d) to afford the free base of the title compound.

MS (ES) m/z 469 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 175 trans4-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinoldihydrochloride Enantiomer E1

This was prepared by the method of Example (129) using aldehyde (148)instead of aldehyde (2c) to afford the free base of the title compound.

MS (ES) m/z 469 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 176(3S,4R)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinoldihydrochloride Enantiomer E2

This was prepared by the methods of Example 74 using piperidine (5c,enantiomer E2) instead of piperidine (5c, enantiomer E1) to afford thefree base of the title compound.

MS (ES) m/z 487 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 177(3S,4R)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]-3-piperidinoldihydrochloride Enantiomer E2

This was prepared by the method of Example 176 using aldehyde as inExample (148) instead of aldehyde (2c) to afford the free base of thetitle compound.

MS (ES) m/z 486 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 178N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinaminedihydrochloride

This was prepared following the method of Example (53j) using2,3-dihydro-1-benzofuran-5-carbaldehyde (commercially available) insteadof aldehyde (2c) to afford the free base of the title compound.

MS (ES) m/z 437 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 1796-{[(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E1

This compound was prepared as described in Example 112 but using AD-mixβ in the dihydroxylation step (99a) and aldehyde (1l) instead ofaldehyde (2c). The compound was eluted from the HPLC Chiralpak AD columnas the major, faster eluting, isomer.

[α]_(D) (25° C.)=+70.8 degrees (c=1%, methanol).

It was converted to the title compound by the method of Example (99).

Example 1806-{[(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E2

This compound was prepared as described in Example 112 but using AD-mixβ in the dihydroxylation step (99a) and aldehyde (1l) instead ofaldehyde (2c) in step (99f). The compound was eluted from the HPLCChiralpak AD column as the minor, slower eluting, isomer.

[α]_(D) (25° C.)=−71.4 degrees (c=1%, methanol).

It was converted to the title compound by the method of Example (99).

Example 1816-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E2

This compound was prepared as described in Example (99) but usingaldehyde (1l) instead of aldehyde (2c) in step (99f). The compound waseluted from the HPLC Chiralpak AD column as the minor, slower eluting,isomer.

[α]_(D) (25° C.)=+8.7 degrees (c=1%, methanol).

It was converted to the hydrochloride by the method of Example (99).

Example 1826-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E1

This compound was prepared as described in Example 99 but using aldehyde(1l) instead of aldehyde (2c) in step (99f). The compound was elutedfrom the HPLC Chiralpak AD column as the major, faster elunting, isomer.

[α]_(D) (25° C.)=−8.3 degrees (c=1%, methanol).

It was converted to the title compound by the method of Example (99).

Example 1836-{[(1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E1

Vinyl-quinoline (97d) was taken through the sequence outlined in Example(99) using AD-mixβ:α (2:1) as a chiral agent for the dihydroxylationstep and aldehyde (1l) instead of aldehyde (2c) in step (99f).

The compound was eluted from the HPLC Chiralpak AD column as the major,faster eluting, isomer.

[α]_(D) (25° C.)=+65.2 degrees (c=1%, methanol).

It was converted to the title compound by the method of Example (99).

Example 1846-{[(1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E2

Vinyl-quinoline (97d) was taken through the sequence outlined in Example(99) using AD-mixβ:α (2:1) as a chiral agent for the dihydroxylationstep and aldehyde (1l) instead of aldehyde (2c) in step (100f).

The compound was eluted from the HPLC Chiralpak AD column as the minor,slower eluting, isomer.

[α]_(D) (25° C.)=−66.3 degrees (c=1%, methanol).

It was converted to the title compound by the method of Example (99).

Example 1856-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanoldihydrochloride Enantiomer E1

Vinyl-quinoline (98d) was taken through the sequence outlined in Example(99) using AD-mixβ:α (2:1) as a chiral agent for the dihydroxylationstep.

The compound was eluted from the HPLC Chiralpak AD column as the major,faster eluting, isomer.

[α]_(D) (25° C.)=+16.4 degrees (c=1%, methanol).

It was converted to the title compound by the method of Example (99).

Example 1866-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanoldihydrochloride Enantiomer E2

Vinyl-quinoline (98d) was taken through the sequence outlined in Example(99) using AD-mixβ:α (2:1) as a chiral agent for the dihydroxylationstep.

The compound was eluted from the HPLC Chiralpak AD column as the minor,slower eluting, isomer.

[α]_(D) (25° C.)=−16.0 degrees (c=1%, methanol).

It was converted to the title compound by the method of Example (99).

Example 1871-[3,8-difluoro-6-(methoxy)-4-quinolinyl]-2-(4[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanoldihydrochloride Enantiomer E2

Vinyl-quinoline (47j) was taken through the sequence outlined in Example(99) using AD-mixα as a chiral agent for the dihydroxylation step.

The compound was eluted from the HPLC Chiralpak AD column as the major,slower eluting, isomer.

It was converted to the title compound by the method of Example (99).

Example 1881-[3,8-difluoro-6-(methoxy)-4-quinolinyl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanoldihydrochloride Enantiomer E1

Vinyl-quinoline (47j) was taken through the sequence outlined in Example(99) using AD-mixα as a chiral agent for the dihydroxylation step.

The compound was eluted from the HPLC Chiralpak AD column as the minor,faster eluting, isomer.

It was converted to the title compound by the method of Example (99).

Example 1891-[3-chloro-6-(methoxy)-4-quinolinyl]-2-{4[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanoldihydrochloride Enantiomer E2

Vinyl-quinoline (4c) was taken through the sequence outlined in Example(99) using AD-mixα as a chiral agent for the dihydroxylation step.

The compound was eluted from the HPLC Chiralpak AD column as the major,slower eluting, isomer.

[α]_(D) (25° C.)=−23.1 degrees (c=1%, methanol).

It was converted to the title compound by the method of Example (99).

Example 1901-[3-chloro-6-(methoxy)-4-quinolinyl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanoldihydrochloride Enantiomer E1

Vinyl-quinoline (4c) was taken through the sequence outlined in Example(99).

The compound was eluted from the HPLC Chiralpak AD column as the major,faster eluting, isomer.

[α]_(D) (25° C.)=+23.6 degrees (c=1%, methanol).

It was converted to the title compound by the method of Example (99).

Example 1911-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanoldihydrochloride Enantiomer E2

Vinyl-naphthyridine (3a) was taken through the sequence outlined inExample (99).

The compound was eluted from the HPLC Chiralpak AD column as the minor,slower eluting, isomer.

[α]_(D) (25° C.)=−7.5 degrees (c=1%, methanol).

It was converted to the title compound by the method of Example (99).

Example 1922-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoro-1-piperidinyl}-1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethanoldihydrochloride Enantiomer E2 (a)7-fluoro-2-(methoxy)-8-(2-oxiranyl)-1,5-naphthyridine

Vinyl-naphthyridine (53h) was treated as in Example (99 a, b and c) butusing AD-mix a in the dihydroxylation step (99a) to afford the product.

MS (ES) m/z 221 (M+H)⁺.

(b) phenylmethyl(3-fluoro-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]-2-hydroxyethyl}-4-piperidinyl)

This was prepared as in Example (99i) using epoxide (a) and piperidine(142d, enantiomer E2).

MS (ES) m/z 473 (M+H)⁺.

(c)2-(4-amino-3-fluoro-1-piperidinyl}-1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethanol

Piperidine (b) was treated as in Example (99h) to afford the product.

MS (ES) m/z 339 (M+H)⁺.

(d) Title Compound

Amine (d) and aldehyde (2c) were treated as in Example (99f) to affordthe free base of the product (88% de).

The compound was eluted from the HPLC Chiralpak AD column as the minor,slower eluting, isomer.

[α]_(D) (25° C.)=+3.4 degrees (c=1%, methanol).

It was converted to the title compound by the method of Example (99).

Example 1932-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoro-1-piperidinyl}-1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethanoldihydrochloride Enantiomer E1

This was prepared as in Example (192), but piperidine (142d, enantiomerE1) in step (192b).

The compound (99.4% de) was eluted from the HPLC Chiralpak AD column asthe major, faster eluting, isomer.

[α]_(D) (25° C.)=+16.3 degrees (c=1%, methanol).

It was converted to the hydrochloride by the method of Example (99).

Example 1947-{[(1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-onedihydrochloride Enantiomer E2

Vinyl-quinoline (47j) and fluoropiperidine (142d, Enantiomer E2) and2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carbaldehyde (aldehydeas in Example 56) were treated as in Example (142e, f and g) to affordthe free base of the title compound.

MS (ES) m/z 518 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 1951-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-N-{[8-(methoxy)-2,3-dihydro-1,4-benzodioxin-6-yl]methyl}-4-piperidinamine(a) 8-(methoxy)-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde

To 3,4-dihydroxy-5-methoxy benzaldehyde (5.0 g, 29.7 mmol) was addedacetone (100 mL), 1,2 dibromoethane (3.56 mL, 41.4 mL), and potassiumcarbonate (2.97 g, 21.5 mmol). The solution was heated to reflux andstirred for 3 days. The solution was then cooled to room temperature andthe solvent removed under reduced pressure. Ethyl acetate was added andthe solution was washed with water and brine. The organic layer was thendried over Na₂SO₄, filtered, and the solvent removed under reducedpressure yielding a crude solid. This was chromatographed on silica gelto yield a white solid (0.890 g, 15%).

MS (ES) m/z 195 (M+H)⁺.

(b) Title Compound

Amine (53i) and aldehyde (a) were treated as in example (53j) to affordthe free base of the compound.

MS (ES) m/z 483 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Example 1961-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-N-[(7-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]-4-piperidinamine(a) 2,3-dihydro-1,4-benzodioxin-6-ol

2,3-Dihydro-benzo{1,4]dioxine-6-carbaldehyde (1.78 g, 10.8 mmol) wasdissolved in CH₂Cl₂ (10 mL). M-chloroperbenzoic acid (4.11 g, 23.9 mmol)was added and the solution heated to reflux for 5 hours. The solutionwas then allowed to cool to room temperature and further cooled in anice bath. The remaining solid was filtered off (excessm-chloroperbenzoic acid) and the solution washed with saturated NaHCO₃solution, water, and brine. This was chromatographed on silica gel toyield a white solid (1.65 g, 100%).

MS (ES) m/z 153 (M+H)⁺.

(b) 6-(methoxy)-2,3-dihydro-1,4-benzodioxin

Alcohol (a) (1.55 g, 10.2 mmol) was dissolved in acetone (10 mL).Dimethyl sulfate (1.06 mL, 11.2 mmol) and potassium carbonate (3.71 g,26.8 mmol) were added and the solution heated to reflux. The solutionwas stirred at reflux for 18 hours. It was then cooled to roomtemperature and concentrated under reduced pressure. The remainingmaterial was diluted with water and extracted several times with EtOAc.The combined organic layers were dried over Na₂SO₄, and evaporated toyield a colorless oil. (0.86 g, 51%).

MS (ES) m/z 167 (M+H)⁺.

(c) 7-(methoxy)-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde

Methoxy-benzodioxine (b) (0.85 g, 5.11 mmol) was dissolved in DMF (0.60mL, 7.66 mmol) and phosphorous trichloride (0.57 mL, 6.14 mmol) wasadded. The solution was heated to 100° C. and allowed to stir for 5hours. The solution was poured into ice water and was brought to pH 14with aqueous sodium hydroxide. A white solid precipitated out, wasfiltered and dried under vacuum to afford the product (0.91 g, 92%).

MS (ES) m/z 195 (M+H)⁺.

(d) 7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde

Aldehyde (c) (0.840 g, 4.33 mmol) was dissolved in dichloromethane (10mL) and boron tribromide (8.66 mL, 8.66 mmol) was added. The solutionwas allowed to stir at room temperature for 1 hour. The reaction wasdiluted with water and brought to pH=7 with a saturated potassiumcarbonate solution. It was then extracted several times withdichloromethane and the combined organic layers washed with brine, driedover Na₂SO₄, and evaporated to yield an off white solid (0.793 g, 100%).

MS (ES) m/z 181 (M+H)⁺.

(e) 7-formyl-2,3-dihydro-1,4-benzodioxin-6-yl trifluoromethanesulfonate

Aldehyde (d) (0.500 g, 2.78 mmol) was dissolved in DMF (10 mL).Triethylamine (0.58 mL, 4.16 mmol) andN-phenyltrifluoromethanesulphonimide (1.09 g, 3.06 mmol) were added. Thesolution was allowed to stir at room temperature for 48 hours. Thereaction was then diluted with dichloromethane and washed with asaturated potassium carbonate solution. The aqueous layer was extractedwith dichloromethane and the combined organic layers washed with brine,dried over Na₂SO₄, and evaporated to yield an oil. This waschromatographed on silica gel to yield a colorless oil with sometriflamide contamination (1.07 g, >100%).

MS (ES) m/z 313 (M+H)⁺.

(f) 7-methyl-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde

Triflate (e) (0.800 g, 2.56 mmol) was dissolved in DMF (10 mL).

Dichlorobis(triphenylphosphine)palladium (II) (0.09 g, 0.13 mmol),lithium trichloride (0.33 g, 7.68 mmol), and tetramethyltin (0.53 mL,3.84 mmol) were added. The solution was heated to 100° C. and stirredfor 1 hour. The solution was cooled to room temperature and diluted withethyl acetate. It was then washed twice with water and brine. Theorganic layer was dried over Na₂SO₄ and evaporated to yield a crudesolid. This was chromatographed on silica gel to yield an off-whitesolid (0.235 g, 52%).

MS (ES) m/z 179 (M+H)⁺.

(g) Title Compound

Amine (53i) and aldehyde (f) were treated as in example (53j) to affordthe free base of the compound.

MS (ES) m/z 467 (M+H)⁺.

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound as a white solid.

Biological Activity

Antimicrobial Activity Assay:

Whole-cell antimicrobial activity was determined by broth microdilutionusing the National Committee for Clinical Laboratory Standards (NCCLS)recommended procedure, Document M7-A6, “Methods for DilutionSusceptibility Tests for Bacteria that Grow Aerobically”. The compoundswere tested in serial two-fold dilutions ranging from 0.016 to 16mcg/mL. Compounds were evaluated against a panel of Gram-positiveorganisms, including Staphylococcus aureus WCUH29, Streptococcuspneumoniae 1629, Streptococcus pyogenes CN 10, and Enterococcus faecalis2. In addition, compounds were evaluated against a panel ofGram-negative strains including Haemophilus influenzae NEMC1, E. coli7623, and Moraxella catarrhalis Ravasio. The minimum inhibitoryconcentration (MIC) was determined as the lowest concentration ofcompound that inhibited visible growth. A mirror reader was used toassist in determining the MIC endpoint.

One skilled in the art would consider any compound with a MIC of lessthan 20 μg/mL to be a potential lead compound. Compounds of the presentinvention have MIC's ≦20 μg/ml versus all the organisms named above.

Examples 1, 3-13, 15-23, 25-32, 34-37, 39-41, 43-45, 47-56, 58-62, 66,68, 70, 72-77, 79, 81, 84-86, 91-100, 105-106, 109-110, 113, 116-118,120, 122-128, 133-135, 138-140, 142-151, 153-165, 167-172, 174, 176-178,181, 182, 187-188, 194 had MIC's ≦2 μg/ml versus all the organisms namedabove.

Rat Infection Model:

Certain compounds of this invention were tested in the rat infectionmodel. Specific pathogen-free male Sprague-Dawley CD rats were used forall bacterial strains. Each therapy group consists of 5 animals.Infection was carried out by intrabronchial instillation of 100 ulbacterial suspension for H. influenzae H128, and 50 ul of bacterialsuspension for S. pneumoniae 1629 via non-surgical intubation. Allcompounds were administered at 1, 7, 24 and 31 hr post infection viaoral gavage. In each experiment, an additional group of animals wasincluded and served as untreated infected controls. Approximately 17 hrafter the end of therapy, the animals were killed and their lungsexcised and enumeration of the viable bacteria was conducted by standardmethods. The lower limit of detection was 1.7 log10 CFU/lungs.

In vivo, activity was observed in infection models in rats versus S.pneumoniae 1629 at doses ranging from 25-100 mg/Kg with oral dosing andfor some compounds versus H. influenzae H128 at doses from 25-100 mg/Kgwith oral dosing. Certain formula (I) compounds showed a greater than 2log drop in viable counts in the lungs compared to non-treated controlsversus S. pneumoniae 1629. Certain compounds of formula (I) showedgreater than a 4 log drop in viable counts in the lungs compared tonon-treated controls versus H. influenzae H 128. The compounds of thisinvention are particularly interesting due to their low toxicity with notoxicity being observed in rats with dosing twice daily for 2 days at 50mg/Kg.

1. A compound according to formula (I):

wherein: Z₁ is Nor CR^(1a); R¹ and R^(1a) are independently selectedfrom H, nitro, halogen, (C₁₋₃)alkylthio, (C₁₋₃)alkyl, and (C₁₋₃)alkoxyoptionally substituted by (C₁₋₃)alkoxy; or R¹ and R^(1a) are joinedtogether to form ethylenedioxy; R^(1b) is H or halogen; with the provisothat when Z₁ is N, then R^(1b) is H and when Z₁ is CR^(1a) then R¹ isnot H; R^(1c) is halogen; AB is CHR⁶—CO or CHR⁶—CH₂; R⁶ is H, NH₂,—CH₂OH, or hydroxy; R³ is up to two substituents selected from H,halogen, (C₁₋₃)alkyl, hydroxy(C₁₋₃)alkyl, CONH₂, COOH, —CH₂CONH₂,—CH₂COOH, —CONHCH₃, and hydroxy in the 3-position optionally substitutedby (C₁₋₃)alkyl; R⁴ is a group —U—R⁵ where R⁵ is a substituted orunsubstituted bicyclic carbocyclic or heterocyclic ring system (A):

containing up to four heteroatoms in each ring in which at least one ofrings (a) and (b) is aromatic; X¹ is C or N when part of an aromaticring or CR¹⁴ when part of a non aromatic ring; X² is N, NR¹³, O,S(O)_(x), CO or CR¹⁴ when part of an aromatic or non-aromatic ring ormay in addition be CR¹⁴R¹⁵ when part of a non aromatic ring; X³ and X⁵are independently N or C; Y¹ is a 0 to 4 atom linker group each atom ofwhich is independently selected from N, NR¹³, O, S(O)_(x), CO and CR¹⁴when part of an aromatic or non-aromatic ring or may additionally beCR¹⁴R¹⁵ when part of a non aromatic ring, Y² is a 2 to 6 atom linkergroup, each atom of Y² being independently selected from N, NR¹³, O,S(O)_(x), CO and CR¹⁴ when part of an aromatic or non-aromatic ring ormay additionally be CR¹⁴R¹⁵ when part of a non aromatic ring; each ofR¹⁴ and R¹⁵ is independently selected from H; (C₁₋₄)alkylthio; halo;(C₁₋₄)alkyl; (C₂₋₄)alkenyl; hydroxy; hydroxy(C₁₋₄)alkyl;mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; trifluoromethoxy; nitro; cyano;carboxy; amino or aminocarbonyl optionally substituted by (C₁₋₄)alkyl;each R¹³ is independently H; trifluoromethyl; (C₁₋₄)alkyl optionallysubstituted by hydroxy, carboxy, (C₁₋₄)alkoxy, (C₁₋₆)alkylthio, halo ortrifluoromethyl; (C₂₋₄)alkenyl; or aminocarbonyl wherein the amino groupis optionally substituted (C₁₋₄)alkyl; each x is independently 0, 1 or2; and U is CO, SO₂ or CH₂; or a pharmaceutically acceptable saltthereof.
 2. A compound according to claim 1 wherein R¹ is F, Cl, OCH₃,methyl, or SCH₃.
 3. A compound according to claim 1 R^(1a) is H, OCH₃,OCH₂CH₂OCH₃.
 4. A compound according to claim 1 wherein R^(1b) is H orF.
 5. A compound according to claim 1 wherein R^(1c) is Cl or F.
 6. Acompound according to claim 1 wherein R³ is H, OH, OCH₃, or CH₂OH.
 7. Acompound according to claim 1 wherein R⁶ is H or OH.
 8. A compoundaccording to claim 1 wherein the group —U— is —CH₂—.
 9. A compoundaccording to claim 1 wherein R⁵ is: benzo[1,2,5]thiadiazol-5-yl;4H-benzo[1,4] thiazin-3-one-6-yl; 2,3-dihydro-benzo[1,4]dioxin-6-yl;benzo[1,2,3]thiadiazol-5-yl; 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl;7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4] oxazin-6-yl;2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl;2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl;3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl;[1,2,3]thiadiazolo[5,4-b]pyridin-6-yl;3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl;7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl; or7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl.
 10. Acompound according to claim 1 which is:6-({1-[(Racemic)-2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-oneDihydrochloride;(Racemic)-1-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-{4-[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-piperidin-1-yl}-ethanolDihydrochloride;{1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amineDihydrochloride;{1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amineDihydrochloride;6-({(cis)-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-oneDihydrochloride Enantiomer 1;6-({(cis)-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-oneDihydrochloride Enantiomer 2;6-({(cis)-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride Enantiomer 1;6-({(cis)-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride Enantiomer 2;6-({(cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-oneDihydrochloride Enantiomer 1;6-({(cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-oneDihydrochloride Enantiomer 2;6-({(cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride Enantiomer 1;6-({(cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride Enantiomer 2;6-({1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one Trihydrochloride;6-({1-[2-(3-chloro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one Trihydrochloride;6-({1-[2-(3-Chloro-6-methoxynaphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one Dihydrochloride;6-({1-[2-(3-chloro-6-methoxynaphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one Dihydrochloride;6-({(trans)-1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]3-hydroxypiperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one Trihydrochlorideenantiomer 2;6-({(trans)-1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]3-hydroxypiperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one Trihydrochlorideenantiomer 2;6-(trans)-1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]3-hydroxypiperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one-Trihydrochlorideenantiomer 1;6-(trans)-1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]3-hydroxypiperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one Trihydrochlorideenantiomer 1;6-({1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]4-hydroxymethylpiperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride;6-({1-[2-(3-Chloro-6-fluoro-5-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride;6-({1-[2-(3-Chloro-6-methyl-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride;{1-[2-(3-Chloro-6-methyl-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amineDihydrochloride;6-({1-[2-(3-Chloro-6-fluoro-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride;{1-[2-(3-Chloro-6-fluoro-quinolin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amineDihydrochloride;6-({1-[2-(3,6-Dichloro-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride;{1-[2-(3,6-Dichloro-quinolin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl-amineDihydrochloride;(cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-4-[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-piperidin-3-olDihydrochloride Enantiomer 1;(cis)-1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-4-[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-piperidin-3-olDihydrochloride Enantiomer 2;6-({1-[2-(3-Fluoro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one dihydrochloride;{1-[2-(3-Fluoro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-aminedihydrochloride;cis-4-[(2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-1-[2-(3-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-3-olEnantiomer 2 dihydrochloride;cis-4-[(2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-1-[2-(3-fluoro-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-3-oldihydrochloride dihydrochloride Enantiomer 1;{1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxyethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amineDihydrochloride Enantiomer 1;6-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride Enantiomer 1;6-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-oneDihydrochloride Enantiomer 2;{6-(trans)-1-[2-(3-Chloro-6-methoxyquinolin-4-yl)ethyl]-3-hydroxypiperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amineEnantiomer 2;(trans)-6-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]-thiazin-3-oneDihydrochloride Enantiomer 2;trans-6-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one Trihydrochloride Enantiomer 2;trans-6-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one dihydrochloride Enantiomer 1;6-({(3R,4r,5S)-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-3,5-dihydroxy-piperidin-4-ylamino)}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-onedihydrochloride;6-({1-[2-(3-Fluoro-6-methoxyquinolin-4-yl)ethyl]piperidin-4-ylamino}methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one dihydrochloride;{1-[2-(3-Bromo-6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amineDihydrochloride;cis-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-4-[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-piperidin-3-olDihydrochloride Enantiomer 1;cis-1-[2-(3-Chloro-6-methoxy-quinolin-4-yl)-ethyl]-4-[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-piperidin-3-olDihydrochloride Enantiomer 2;1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinaminedihydrochloride;7-{[(1-{2-[3,8-Difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-onedihydrochloride;6-{[(1-{2-[3,8-Difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedinydrochloride;6-{[(1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride;1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-([1,3]dioxolo[4,5-c]pyridin-6-ylmethyl)-4-piperidinaminedihydrochloride;{1-[2-(9-Chloro-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-aminedihydrochloride;N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinaminedihydrochloride;N-(2,3-Dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinaminedihydrochloride;6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride;7-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-onedihydrochloride;3-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-8-hydroxy-1(2H)-isoquinolinone dihydrochloride;3-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-5H-pyridazino[3,4-b][1,4]thiazin-6(7H)-onedihydrochloride;6-[({1-{2-[3-Fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride;N-(2,3-Dihydro[1,4]oxathiino[2,3-c]pyridin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinaminedihydrochloride;1-{2-[3-Fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-N-([1,3]oxathiolo[5,4-c]pyridin-6-ylmethyl)-4-piperidinaminedihydrochloride;7-Fluoro-N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamidedihydrochloride;N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamidedihydrochloride;N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide;N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxamide;(3R,4S)-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinoldihydrochloride Enantiomer 1;6-{[((3R,4S)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride;6-{[((3R,4S)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride;(3R,4S)-4-[(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinoldihydrochloride;6-{[((3S,4R)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer 2;N-((3S,4R)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamidehydrochloride Enantiomer 2;7-{[((3R,4S)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-onedihydrochloride Enantiomer 1;6-{[((3R,4S)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer 1;(3R,4S)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinoldihydrochloride dihydrochloride Enantiomer 1;6-{[((3R,4S)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride;N-[(4-fluoro-1H-benzimidazol-2-yl)methyl]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinamine;1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(1,5,6,7-tetrahydro-1,8-naphthyridin-2-ylmethyl)-4-piperidinaminedihydrochloride;N-(3-cinnolinylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinaminedihydrochloride;N-(2,1,3-benzothiadiazol-5-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinaminedihydrochloride;1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-([1,3]thiazolo[5,4-b]pyridin-6-ylmethyl)-4-piperidinaminedihydrochloride;N-(3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinaminedihydrochloride;N-(1,3-benzothiazol-5-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinaminedihydrochloride;1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-([1,2,3]thiadiazolo[5,4-b]pyridin-6-ylmethyl)-4-piperidinaminedihydrochloride;7-{[(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-onedihydrochloride;N-(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinaminedihydrochloride;N-(2,3-dihydro[1,4]oxathiino[2,3-c]pyridin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinaminedihydrochloride;4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-methyl-4-piperidinecarboxamidedihydrochloride;4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinecarboxamidedihydrochloride;4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-N-methyl-4-piperidinecarboxamidedihydrochloride;4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinecarboxamidedihydrochloride;1-{2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-4-piperidinecarboxamidedihydrochloride;(4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)methanoldihydrochloride;N-[1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-(hydroxymethyl)-4-piperidinyl]-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamidehydrochloride;N-[1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxamidehydrochloride;N-(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamidehydrochloride;7-{[((3R,4S)-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-onedihydrochloride Enantiomer 1;6-{[((3R,4S)-1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer 1;(3R,4S)-1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinoldihydrochloride;2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl)-1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethanolDihydrochloride Hydrate Enantiomer 1;2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl)-1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethanolDihydrochloride Hydrate Enantiomer 2; racemic,cis4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-(2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinyl)methanoldihydrochloride;racemic,cis-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-(2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinecarboxylicacid dihydrochloride;racemic,cis-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinecarboxamidedihydrochloride;1-{2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-N-[(6-oxido-2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-yl)methyl]-4-piperidinaminedihydrochloride;6-{[(1-{2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]-3-hydroxypropyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride;6-[({1-[2-(3,6-difluoro-4-quinolinyl)ethyl]-4-piperidinyl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride;1-[2-(3,6-difluoro-4-quinolinyl)ethyl]-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinaminehydrochloride dihydrochloride;6-[({1-[2-(3,6-difluoro-4-quinolinyl)ethyl]-4-piperidinyl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride;6-{[(1-{2-[3-chloro-6-fluoro-5-(methoxy)-4-quinolinyl]-1-methylethyl)-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride;1-{2-[3-chloro-6-fluoro-5-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinaminedihydrochloride;1-[2-(6-chloro-3-fluoro-4-quinolinyl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-N-methyl-4-piperidinecarboxamidedihydrochloride;2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl)-1-[3-fluoro-6-(methoxy)-4-quinolinyl]ethanoldihydrochloride Enantiomer 2;6-{[trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E2;6-{[trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E2;trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinoldihydrochloride Enantiomer E2;6-{[trans-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one-dihydrochlorideEnantiomer E2;trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-piperidinoldihydrochloride;N-trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamidehydrochloride Enantiomer E2;N-trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxamidehydrochloride Enantiomer E2; racemic,trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-3-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride;Trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-methyl-3-piperidinoldihydrochloride;6-{[trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E1;Trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-3-piperidinoldihydrochloride;6-{[trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E2;Trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-3-piperidinoldihydrochloride;N-(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinaminedihydrochloride;{[(1-{2-[3-Fluoro-6-(methoxy-5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-3,4-dihydro-1,8-naphthyridin-2-(1H)-one;7-{(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinyl)amino]methyl}-2,3-dihydro-1,5-benzothiazepin-4(5H)-one;trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinoldihydrochloride Enantiomer E1;6-{[(-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride;trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-oneEnantiomer E1;trans-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-piperidinoldihydrochloride;trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride;trans-N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamidehydrochloride Enantiomer E1;trans-N-((3R,4R)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxamideIsomer E1 hydrochloride;trans-N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)-2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxamideIsomer E1 hydrochloride;6-{[trans-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-oneEnantiomer E1;6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride;6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride;N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinaminedihydrochloride;N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)-2,3-dihydro-1,4-benzodioxin-6-sulfonamide;cis-6-{[(1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer 1;cis-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-3-fluoro-4-piperidinaminedihydrochloride Enantiomer1;cis-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-3-fluoro-4-piperidinaminedihydrochloride Enantiomer 2;cis-6-{[(1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride, Enantiomer 1;cis-6-{[(1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride, Enantiomer 2;cis-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-3-fluoro-4-piperidinaminedihydrochloride, Enantiomer 1;cis-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-3-fluoro-4-piperidinaminedihydrochloride, Enantiomer 2;cis-6-([(−1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride, Enantiomer 1;cis-6-([(−1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride, Enantiomer 2;cis-N-(1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamidehydrochloride Enantiomer 1;6-{[((3S,4R)-1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-hydroxy-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E2;trans-6-({1-[2-(3-Chloro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-hydroxy-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one trihydrochloride Enantiomer 1;trans-1-{2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinolEnantiomer 1;trans-1-{2-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinolEnantiomer 2;2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}-1-[3-fluoro-6-(methoxy)-4-quinolinyl]ethanoldihydrochloride Enantiomer 1;N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinamine;(3S,4R)-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinoldihydrochloride Enantiomer 2;(3R,4S)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-[([1,3]oxathiolo[5,4-c]pyridin-6-ylmethyl)amino]-3-piperidinoldihydrochloride Enantiomer E1;6-{[(1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one;1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-N-(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinamine;(3S,4R)-1-[2-(3,6-dichloro-4-quinolinyl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinoldihydrochloride Enantiomer E2;6-[({(3S,4R)-1-[2-(3,6-dichloro-4-quinolinyl)ethyl]-3-hydroxy-4-piperidinyl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E2;(3S,4R)-1-[2-(3-chloro-6-fluoro-4-quinolinyl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinoldihydrochloride Enantiomer E2;6-[({(3S,4R)-1-[2-(3-chloro-6-fluoro-4-quinolinyl)ethyl]-3-hydroxy-4-piperidinyl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E2;N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)-2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxamidedihydrochloride;N-(1-({2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxamide;N-(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-methyl-4-piperidinyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide;trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-3-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E1;trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-3-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E1;trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-3-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E2;trans-6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-3-methyl-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride Enantiomer E2;trans-4-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-piperidinolhydrochloride Enantiomer E1; trans4-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinoldihydrochloride Enantiomer E2;trans-4-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-3-piperidinoldihydrochloride Enantiomer E1;(3S,4R)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-piperidinoldihydrochloride Enantiomer E2;(3S,4R)-1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-4-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]-3-piperidinoldihydrochloride Enantiomer E2;N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-4-piperidinaminedihydrochloride;6-{[(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E1;6-{[(1-{2-[3-fluoro-6-(methoxy)-4-quinolinyl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E2;6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E2;6-{[(1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E1;6-{[(1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E1;6-{[(1-{2-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]-2-hydroxyethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride Enantiomer E2;1-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanoldihydrochloride Enantiomer E1;1-[3-chloro-8-fluoro-6-(methoxy)-4-quinolinyl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanoldihydrochloride Enantiomer E2;1-[3,8-difluoro-6-(methoxy)-4-quinolinyl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanoldihydrochloride Enantiomer E2;1-[3,8-difluoro-6-(methoxy)-4-quinolinyl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanoldihydrochloride Enantiomer E1;1-[3-chloro-6-(methoxy)-4-quinolinyl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanoldihydrochloride Enantiomer E2;1-[3-chloro-6-(methoxy)-4-quinolinyl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanoldihydrochloride Enantiomer E1;1-[3-chloro-6-(methoxy)-1,5-naphthyridin-4-yl]-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}ethanoldihydrochloride Enantiomer E2;2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoro-1-piperidinyl}-1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethanoldihydrochloride Enantiomer E2;2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoro-1-piperidinyl}-1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethanoldihydrochloride Enantiomer E1;7-{[(1-{2-[3,8-difluoro-6-(methoxy)-4-quinolinyl]ethyl}-3-fluoro-4-piperidinyl)amino]methyl}-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-onedihydrochloride Enantiomer E2;1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-N-{[8-(methoxy)-2,3-dihydro-1,4-benzodioxin-6-yl]methyl}-4-piperidinamine;and1-{2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]ethyl}-N-[(7-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]-4-piperidinamine;or a pharmaceutically acceptable salt thereof.
 11. A process forpreparing compounds of formula (I), and pharmaceutically acceptablederivatives thereof, which process comprises reacting a compound offormula (IV) with a compound of formula (V):

wherein Z¹′, R^(1′), R^(1b′), R^(1c′) and R^(3′) are Z¹, R¹, R^(1b),R^(1c) and R³ as defined in formula (I) or groups convertible thereto;Q¹ is NHR^(4′) or a group convertible thereto wherein R^(4′) is R⁴ asdefined in formula (I) or groups convertible thereto and Q² is H orR^(3′) or Q¹ and Q² together form an optionally protected oxo group; (i)X is A′-COW, Y is H; (ii) X is CH═CH₂, Y is H; (iii) X is oxirane, Y isH; (iv) one of X and Y is CO₂R^(y) and the other is CH₂CO₂R^(x); inwhich W is a leaving group, e.g. halo or imidazolyl; R^(x) and R^(y) are(C₁₋₄)alkyl; A′ is A as defined in formula (I), or groups convertiblethereto; and oxirane is:

and thereafter optionally or as necessary converting Q¹ and Q² toNHR^(4′); converting A′, Z^(1′)R^(1′), R^(1b′), R^(1c′), R^(3′), andR^(4′) to A, Z¹, R¹, R^(1b), R^(1c), R³, and R⁴; converting A-B to otherA-B, interconverting R¹, R^(1b), R^(1c), R³, and/or R⁴, and/or forming apharmaceutically acceptable derivative thereof.
 12. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutically acceptable carrier.
 13. A method of treating bacterialinfections in mammals which comprises administrating to a mammal in needthereof an effective amount of a compound according to claim 1.